amino acids, peptides and proteins in organic chemistry (origins and synthesis of amino acids) ||...

13Synthesis of g- and d-Amino AcidsAndrea Trabocchi, Gloria Menchi, and Antonio Guarna

13.1Introduction

An area of significant importance that provides new dimensions to the field ofmolecular diversity and drug discovery is the area of peptidomimetics [1]. Biomedicalresearch has reoriented towards the development of new drugs based on peptides andproteins, by introducing both structural and functional specific modifications, andmaintaining the features responsible for biological activity. As a part of this researcharea, unnatural amino acids are of valuable interest in drug discovery and their use asnew building blocks for the development of peptidomimetics with a high structuraldiversity level is of key interest. In particular,medicinal chemistry has taken advantageof theuse of aminoacidhomologs to introduce elements of diversity for the generationof new molecules as drug candidates in the so-called �peptidomimetic approach�,where a peptide lead is processed into a new nonpeptidic molecule. The additionalmethylenic unit between the N- and C-termini in b-amino acids results in an increaseof the molecular diversity in terms of the higher number of stereoisomers andfunctional group variety, and many synthetic approaches to the creation of b-aminoacids have been published. There is great interest in these as a tool for medicinalchemistry [2] and in the field of b-peptides generally [3]. The g - and d-amino acids havegarneredsimilar interest. Inparticular, the foldingproperties of g- [4] andd-peptides [5]have been investigated, as they have been proved to generate stable secondarystructures. Thehomologationofa-amino acids into g - and d-units allows anenormousincrease of the chemical diversity within the three and four atoms between the aminoand carboxyl groups. Thus, additional substituents and stereocenters expandthe number of compounds belonging to the class of g- and d-amino acids. g -Aminoacids have been reported both in linear form, and with the amino and carboxylgroups separated or incorporated in a cyclic structure. In the case of d-amino acids,five- and six-membered rings have been mainly reported having two substituentsvariously tethered between the amino and carboxyl groups. Moreover, bicyclicand spiro compounds have been reported as constrained d-amino acids, especiallyin the field of peptidomimetics. The synthetic approaches for the preparation of

Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.1 – Origins and Synthesis of Amino Acids.Edited by Andrew B. HughesCopyright � 2009 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32096-7

j527

g- and d-amino acids take into account a wide array of tools, including asymmetricsynthesis, enzymatic processes, resolution procedures, and the use of building blocksfrom the chiral pool. Among the use of chiral auxiliaries, pantolactone [6], Evans�oxazolidinone [7], and natural product derivatives [8] have been commonly applied forstereoselective processes, such as alkylations, double-bond additions, and aldolcondensations. The building blocks from the chiral pool are usually natural aminoacids as starting precursors for homologation to g- and d-amino acid structures, andcarbohydrates particularly suited to the preparation of sugar amino acids (SAAs).Modern stereoselective syntheses include the use of chiral metal complexes ascatalysts in hydrogenations or double-bond additions, and more recently the applica-tion of proline- and cinchona-based organocatalysts. Also, enzymatic syntheses havebeen reported as a tool for desymmetrization or selective transformation of esterfunctions. The amino group is typically obtained directly from reduction of azides,cyano, or nitro groups, or from carboxamides and carboxylic acids throughHoffmannandCurtius degradations, respectively. The carboxylic group is achieved by hydrolysisof esters, cyanides, or oxazolines as protecting groups, or by oxidations of hydro-xymethyl moieties.

13.2g-Amino Acids

One of the major goals in the development of g-amino acids is the generation ofg-aminobutyric acid (GABA) analogs, as this molecule is a neurotransmitter in thecentral nervous system of mammals and its deficiency is associated with severalneurological disorders, such as Parkinson�s and Huntington�s diseases [9]. Thus, agreat deal of interest in the synthesis of GABA analogs is well documented, with theaim tomodulate the pharmacokinetic properties and the selectivity of various GABAreceptors. Also, b-hydroxy-g-amino acids constitute the family of statines, which havebeen developed as inhibitors of aspartic acid proteases, thus finding importantapplications in the therapy of many infectious diseases, including HIV and malaria,and also Alzheimer�s disease and hypertension. Finally, g -amino acids have beendeveloped so as to constrain peptide sequences into b- and g-turns, and to producenew carbohydrate-based amino acids and oligomers. The asymmetric synthesis ofmany structurally diverse g -amino acids has been extensively reviewed, comprisinglinear hydroxy-functionalized molecules and cyclic and azacyclic systems [10]. Themost representative examples of the various synthetic approaches are describedherein so as to cover the huge area of synthetic methodologies leading to g-aminoacids.

13.2.1GABA Analogs

The inhibitor neurotransmitter GABA has served as a structural template for anumber of substances that have effects on the central nervous system [11]. Acommon

528j 13 Synthesis of g- and d-Amino Acids

strategy to designmany of these compounds is tomanipulate the GABAmolecule inorder to increase its lipophilicity, thus allowing it to gain access to the central nervoussystem [12]. In particular, the incorporation of the third carbon atom of GABA into acyclohexane ring produced the anticonvulsant agent gabapentin (Neurontin) (1).Other GABA analogs such as vigabatrin (Sabril) (2) [13] and baclofen (Kemstro andLioresal) (3) [14] have been reported as enzyme inhibitors of the GABA metabolicpathway, while gabapentin activity results from a different biological pathway(Scheme 13.1).A number of alkylated analogs have been synthesized and evaluated in vitro for

binding to the gabapentin binding site [15]. The synthetic approach, shown inScheme 13.2, is exemplified by 4-methyl cyclohexanone (4), which is allowed toreact with a cyanoacetate to give thea,b-unsaturated ester (5), followed by insertion ofa second cyano group, and final conversion into spiro lactam (6). The insertion of the

CO2HNH2

HO2C NH2

NH2HO2C

Gabapentin1

αγ

H2N CO2H

GABA

Vigabatrin2

Baclofen

3

Cl

Scheme 13.1

OCO2EtNC CN

NC

CO2EtNC

HNO

HCl.H2N CO2H

NCCH2CO2Et KCN

EtOHHCl

H2Ni RaneyHCl

αγ

4 5

67

Scheme 13.2

13.2 g-Amino Acids j529

secondCNoccurs so as tominimize the unfavorable diaxial interactionswithC-3 andC-5 protons, thus placing both the second CN and the 4-methyl group in axialpositions. Acid-mediated ring opening of (6) produces g-amino acids of generalformula (7) as gabapentin analogs.Compound (11), stereoisomeric to (7), is obtained byWittig olefination of 4-methyl

cyclohexanone (8), to give cyclohexylidenes (9). Insertion of nitromethyl function atthe b-position from the less hindered equatorial direction, followed by catalytichydrogenation, gives the spiro lactam (10) (Scheme 13.3).The synthesis of (S)- and (R)-2MeGABA (17a and 17b, respectively) has been

reported by Duke et al. starting from tiglic acid (12), through insertion of the aminogroup via the N-bromosuccinimide/potassium phthalimide procedure [6a]. Theracemic carboxylic acid (13) was then coupled with (R)-pantolactone (14) to allowthe resolution, via chromatographic separation of the resulting diastereoisomers(15 and 16) (Scheme 13.4), and the achievement of the title enantiomeric g-aminoacids after ester hydrolysis and phthalimide deprotection.Another example of synthesis employing chiral auxiliaries is the preparation of

b-aryl-GABAs (22) starting from benzylidenemalonates (18) (Scheme 13.5) [8d].g-Lactam (19) resulting from addition of KCN to the double bond, followed byreduction to the corresponding amine and subsequent alkaline cyclization, wascoupled with (R)-phenylglycinol to allow the chromatographic separation of theresulting diastereomeric amides (20). Final amide hydrolysis to remove the chiralauxiliary, followed by decarboxylation produced the lactam (21), which was convertedto enantiopure g -amino acid (22) by alkaline hydrolysis.The synthesis of pregabalin (S)-(25) (Scheme 13.6) was achieved through asym-

metric hydrogenation in the presence of (R,R)-(Me-DuPHOS)Rh(COD)BF4 (COD¼cyclooctadiene) (23) as chiral catalyst [16]. The intermediate nitrile compound (24)was then reduced by hydrogenation over nickel to achieve the corresponding g-aminoacid (25).

O CO2Et CO2Et

HNO

HCl.H2N CO2H

(Et2O)2P(O)CH2CO2Et MeNO2

H2Ni Raney

HCl

O2N

αγ

98

1011

Scheme 13.3


The Ru(II)-(S)-BINAP [BINAP¼ 2,20-bis(diphenylphosphino)1,10-binaphthyl]complex has been employed as catalyst for the asymmetric reduction of the ketogroup of keto ester (26) in 96%e.e. Subsequent treatment of theOHgroup of (R)-(27)with PBr3 and NaCN allowed introduction of the cyano group as an amine precursor.Finally, reductive cyclization to the corresponding g -lactam (R)-(28) was achieved byNaBH4 andNiCl2, followed by acid hydrolysis to obtain the title g-amino acid (R)-(29)(Scheme 13.7) [17].

MeMe

O

OEt

OO

HOMe Me

Me

O

OEtPhthN

Me

OPhthN

OO

OMe Me

Me

OPhthN

OO

OMe Me

Me

OH2N

OHMe

OH2N

OH

1. NBS/CCl42. PhthN-K+/DMF

(R)-Pantolactone

R

3. H2, Pd/C4. HCl, AcOH

1. SOCl2/C6H62. (R)-Pantalactone3. chromatographic separation

RR RS

(S)-2MeGABA (R)-2MeGABA

12(+/-)-13

14

15 16

17a 17b

Scheme 13.4

PhCO2Et

CO2Et NH

Ph CO2H

ONH

Ph

O

NH

OH

PhO

NH

Ph

O

O

OHBocHN

Ph

1. KCN2. H2, Ra-Ni

3. KOH, THF

1. (R)-Phenylglycinol DCC/HOBT2. Chromatography

1. 6N HCl, THF2. nBuOH3. K2CO3/MeOH

(R)-(R)-

1. (Boc)2O, DMAP/Et3N2. 1N LiOH/THF

18 19 20

2122

Scheme 13.5


As an example of enzymatic asymmetric synthesis, the preparation of (R)-baclofen(3) using microbiological mediated Baeyer–Villiger oxidation has been reported(Scheme 13.8) [18]. Specifically, oxidation of cyclobutanone (30) produced thecorresponding g -lactone (R)-31 with high enantioselectivity. Subsequent manipula-tion of (R)-31 consisted of regioselective ring opening using iodotrimethylsilane,followed by treatmentwith sodiumazide, andfinally catalytic hydrogenation to affordthe amino group of the title compound (R)-3.The use of sugars as building blocks from the chiral pool has been applied to N-D-

mannose substituted nitrones (32) in the reaction with acrylates using SmI2, givingthe corresponding adduct (33) in 90% e.e. with the major (R) diastereoisomer(Scheme 13.9) [19]. The same reaction when applied to N-D-ribose substitutednitrones (34) afforded the corresponding g-substituted-a-amino acid precursor(35) with opposite (S) configuration, indicating the choice of sugar nitrone as a toolfor obtaining either (R) or (S) enantiomers.One example of the application of a-amino acids as building blocks from the chiral

pool to obtain g-substituted g-amino acids was achieved through double Arndt–Eistert

CN

CO2

CN

CO2 CO2H

NH2

H2, 54 psi

97.7% ee

1. H2, Ni2. AcOH

(S)- 25

t-BuNH3

t-BuNH3

24

(R,R)-(Me-DuPHOS)Rh(COD)BF4 (23)

Scheme 13.6

Cl

OEt

O O

Cl

OEt

OOH

Cl

OEt

OBr

Cl

OEt

OCN

Cl

HN

O

Cl

CO2H

NH2

Ru(II)-(S)-BINAPH2, 800 psi

(R)-27 96% ee

PBr3/Py

NaCN, DMF NaBH4, MeOH

(R)-28

6M HCl

100 °C

(R)- 29, 90% ee

26

NiCl2.6H2O

Scheme 13.7


homologation (Scheme 13.10) [20]. The b-amino acid was obtained from the corre-sponding Cbz-a-amino acid (36) by reactionwith oxalyl chloride and diazomethane togive the diazoketone (37). Subsequent Wolff rearrangement of (37) using AgOBz andEt3N in MeOH afforded the fully protected Cbz-g-amino acid (38).

O

Cl Cl

O O

Cl

CO2Et

N3

Cl

CO2EtHCl.H2N

C. echimulata

(R)-31 99% ee

1. TMSI/EtOH2. NaN3/DMF

1. 2M NaOH2. HCl

3. H2, Pd/C4. HCl

30

99% ee(R)-Baclofen 3 99% ee

Scheme 13.8

N

R H

O O

OO

O

O

N

R

O HO

OO

O

O

O

OnBu

CO2nBu

SmI2

N

R H

O O

OO

MeN

R

O

OO

Me

O

OnBu

CO2nBu

SmI2

R

S

HO

95:5 dr32 33

34 35

R = c-Hexyl; i-Pr; o-Penthyl; 2-Ethylbutyl

R = c-Hexyl; i-Pr; o-Penthyl

Scheme 13.9


13.2.2a- and b-Hydroxy-g-Amino Acids

Ley et al. recently reported an attractive approach to chiral a-hydroxy-g -amino acidsusing Michael addition of a chiral glycolic acid-derived enolate to the correspondinga,b-unsaturated carbonyl compound or nitro olefin [21]. Specifically, lithium enolateMichael addition of butane-2,3-diacetal desymmetrized-glycolic acid (39) to nitroolefins affords the correspondingMichael adducts (40) with high diastereoselectivity.Subsequent hydrogenation of the nitro group lead to g-lactams (41), which can beconverted to a-hydroxy-g -amino acids (42) (Scheme 13.11).Reetz et al. have shown a route to prepare a-hydroxy-g -amino acids starting from

L-amino acids, by stereoselective [2,3]-Wittig rearrangement [22]. The use of tetra-methylethylenediamine in the formation of the lithiumenolate led to the preferentialformation of one of the four possible diastereoisomers (43), as shown inScheme 13.12. Compound (44) displays intramolecular hydrogen bonds arisingfrom the amide group and the alcohol function as a conformational feature of theg-turn mimetic.

Bn

NHCbzOH

OBn

NH O

OH Bn

NH O

Bn

NHCbz

O

OCH3Bn

NH2

O

OH

1.(COCl)22. CH2N2

NaOH/H2OH2, Pd/C

PhCO2Ag, Et3N/MeOH36

37

38

N2

Cbz Cbz

Bn

NHCbz

O

OH

Scheme 13.10

OO

O

O

O

1. LiHMDS

2.

OO

O

O

O

Ph

1. Ni Raney2. SiO2

NO2

NH

O

OMeO

O

Ph

MeONH2

O

OH

Phα

γ

PPh3,HBr

MeOH

39

4142

40Ph

NO2

Scheme 13.11


The structural class of b-hydroxy-g -amino acids in recent years has been the objectof much attention, especially in connection with the development of new pharma-ceuticals based on protease inhibitors [1b,23]. Statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (45) (Scheme 13.13), is an essential component of pepstatine, anatural hexapeptide antibiotic, which acts as an inhibitor of renin, pepsin andcathepsin D aspartyl proteases [24]. The a- and b-hydroxy-g -amino acids derivativesare among the most synthesized g-amino acids, as these key structural units arefound in molecules showing several types of pharmacological activity, includingantibacterials and anticancer drugs [25]. The low selectivity of pepstatine has inducedthe development of more specific synthetic analogs. In particular, the substitution ofthe isobutylmoiety of statine by themore lipophilic cyclohexylmethyl substituent hasled to the widely used analog cyclohexylstatine (46), which is a key component ofrenin inhibitors (Scheme 13.13).Castejón et al. reported stereodivergent and enantioselective approaches to statine

analogs, which allows the synthesis of any of the four possible stereoisomers (47–50)of a given b-hydroxy-g -amino acid in fully protected form, ultimately arising from asingle allylic alcohol (51) of (E) configuration (Scheme 13.14). This approach relies onthe ready availability of anti N-protected-3-amino-1,2-diols of general structure (52)and (53) in high enantiomeric excess [26].The anti b-hydroxy-g-amino acids (48) and (50) have been obtained starting from

3-amino-1,2-alkanediols (52) and (53) by introduction of a carboxyl-synthetic equiva-lent at C-1, followed by selective activation of this position (Scheme 13.15). Thismethodology is also applicable to the preparation of syn amino acids (47) and (49),provided that a configuration inversionat theC-2position is included in the sequence.

CHOBocHN

R

BocHN

R

CO2Et

BocHN

R

OCO2

t Bu

1.DIBAH, BF3.OEt2

2.BrCH2CO2tBu

BocHN

R OH

CO2ButLDA

TMEDA

Ph3PCHCO2Et

αγ

44 43

R = Me, CH2Ph, i-Pr, i-Bu

Scheme 13.12

Me

Me NH2

CO2HOH

NH2

CO2HOH

Statine Cyclohexylstatine

αγ

αγ

45 46

Scheme 13.13


A general method for the synthesis of a- and g -alkyl-functionalized b-hydroxy-g-amino acids was described by Kambourakis et al. [27]. Some methods for thesynthesis of such compounds are based on low yielding resolutions of esterderivatives using lipases [28]. The synthesis of both classes of amino acids accordingto Kambourakis et al. proceeds through a common chiral alcohol intermediate (55),which is generated from ketone diester (54) via the action of a nicotinamide-dependent ketoreductase. Regioselective chemical or enzymatic hydrolysis, followedby rearrangement under Hofmann or Curtius conditions, gives the final amino acidg- and a-alkyl functionalized products (56) and (57), respectively. The chemo-enzymatic method for the synthesis of individual diastereomers of b-hydroxy-g-amino acids, using nonchiral starting materials, has a key step in the form of adiastereoselective enzymatic reduction that generates two stereocenters in a singlestep: the keto diester is reduced diastereoselectively to form the hydroxyl diester

R CO2H

N

OHR CO2H

N

OHR CO2H

N

OHR COOH

N

OH

R OH

N

OH

R OH

N

OHR OH

αγ

αγ

5152 53

47 4948 50

H Boc H Boc H Boc BocH

BocHBocH

R = Me, Ph, c-hexylmethyl

Scheme 13.14

R OH

NH

OHR CO2H

N

OHProtection

ActivationSubstitution

12

3

R OH

HN

OHR CO2H

N

OHProtection

ActivationSubstitution

12

3

Inversion

Boc HBoc

BocHBoc

anti :

syn :

R = Me, Ph, c-Hexylmethyl

Scheme 13.15


intermediate (55) in high yield by the action of a ketoreductase enzymewhich sets theabsolute stereochemistry in the molecule (Scheme 13.16).Selective enzymatic transesterification of racemic O-acetyl cyanohydrin (58)

using the yeast Candida cylindracea lipase (CCL) afforded enantiopure (R)-cyanohy-drin (59a), and the enriched (S)-O-acetyl-cyanohydrin (59b) (Scheme 13.17). Subse-quent treatment of (59b) with porcine pancreas lipase (PPL) gave enantiopure(S)-cyanohydrin (60). Reduction of the cyano group in (R)-61a and (S)-60 usingborane–tetrahydrofuran (THF) complex and NiCl2 produced the correspondingenantiomers of (S)-4-amino-3-hydroxybutanoic acid (GABOB; 61a and 61b,respectively) [29].The chemoselective reduction of (R)-malic acid dimethyl ester with borane–Me2S

complex in the presence of NaBH4 gave the corresponding diol (R)-62. Subsequentmanipulation of the primary hydroxylic group to introduce an azide consisted of SN2reaction on the preformed tosylate (R)-63 to give (R)-64, which by hydrogenation inthe presence of Boc2O generated the corresponding protected b-hydroxy-g-aminoester (R)-65 in one pot (Scheme 13.18) [30].

EtO2C CO2EtO

XR EtO2C CO2EtO

R

Ketoreductase

EtO2C CO2EtOH

R

Chemical or Enzymatic hydrolysis

ChemicalhydrolysisHO2C CO2H

OH

R

EtO2C CO2HOH

R

HO2C CO2EtOH

R

EtO2C NH2

OH

R

H2N CO2EtOH

R

1. Protection2. Rearrangement

1. Protection2. Rearrangement

ααγ

γ

54

55

56 57

R = -CH2CH(CH3)2, -(CH2)2CH(CH3)2, -CH2Ph, -(CH2)2Ph

Scheme 13.16


A stereoselectivemethod for the synthesis of g-substituted-g-amino acids from thecorresponding a-amino acids using the a-amino acyl Meldrum�s acid (66) asprecursor was described by Smrcina (Scheme 13.19) [31]. Changing the order ofNaBH4 reduction–lactam ring formation allows the introduction of a hydroxylfunction at b-position. Final basic ring opening of the five-membered lactam givesthe corresponding g-amino acids (67) and (68).

OAc

NC

O

OEt

OH

NC

O

OEt

OAc

NC

O

OEt

OH O

OEtH2N

OH

NC

O

OEt

OH O

OEtH2N

Lipase CCL

(R)-59a (S)-59b

BF3.THF,NiCl2.6H2O

BF3.THF,NiCl2.6H2O

Lipase PPL

(R)-GABOB 61a (S)-60

(S)-GABOB 61b

58

Scheme 13.17

OH O

OMeMeO

O

OH O

OMeHO

OH O

OMeTsO

OH O

OMeN3

OH O

OMeBocHN

(R)-Malic acid

BH3.DMS

NaBH4 90%

TsCl, Py

64%(R)-62

NaN3, DMF

83%(R)-63 (R)-64

H2, Pd/C

(Boc)2O 87% (R)-65

Scheme 13.18


13.2.3Alkene-Derived g-Amino Acids

Several nitro-olefin derivatives have been reported as good intermediates for thesynthesis of g-amino acids. In particular, variously functionalized nitrooxazolineshave been described as versatile intermediates for the synthesis of g-amino acids byconverting the nitro and oxazoline groups of (69) into the corresponding amino andcarboxylic functions as in (70) (Scheme 13.20) [32].Another example of the preparation of enantiomerically enriched g-amino acids

from unsaturated compounds involves a palladium-catalyzed allylic nucleophilesubstitution [33]. In particular, an oxazoline-based phosphine ligand catalyst is usedto effect an efficient enantioselective reaction, such as the conversion of the standardallyl acetate (71) into the substitution product (72) (Scheme 13.21).Subsequent conversion of (72) into the corresponding g -amino acid (75) is

achieved with a Krapcho decarboxylation reaction on the cyano ester (72), givingthe corresponding nitrile (73), that is successively reduced to give (74). Finally, an

BocHNOH

O

R

BocHNO

RO

OO

O

BocN

O

R O

BocHN

RO

OO

O

BocN

O

R OH

BocN

O

R

BocHN CO2H

Meldrum'sacid

AcOEtreflux

NaBH4

R

OH

NaOH

BocHN CO2H

R

NaBH4

Toluenereflux

NaOH

α αγ γ

66

6867

R= Bn, i-Bu, i-Pr, BnOCH2-, BnSCH2-, BnOCOCH2-

Scheme 13.19


oxidative cleavage of the alkene (74) affords the carboxylic acid (75). Otaka et al.describe facile access to functionalized g-amino acid derivatives for the design offoldamers via SmI2-mediated reductive coupling between g-acetoxy-a,b-enoate (76)and N-Boc-a-amino aldehydes (77) (Scheme 13.22). The reaction is reported to givediastereomeric mixtures of g-amino acids (78) in good yields, although without anydiastereoselection [34]. The additional functional groups present on the resultingg-amino acid derivatives may allow further chemical transformations to increase thechemical diversity.

Cu(CN)Li2

N

O2

R NO2

R2R1 N

O R2R1

NO2RHO

O R2R1

NH2R

α

γ

7069

R = H or alkyl; R1 = H or alkyl; R2 = H or alkyl

Scheme 13.20

Ph R

OAc

Ph RNuH, NaH

10% cat*2,5% [Pd(allyl)Cl]2

PhCO2MeNC

yield 74-90%ee 86-96%

Ph

NaClwet DMSO

Ph R

CNPh

Ph R

Ph NH2 LiAlH4

HO2C

R

NH2α

γ

cat*: ligand

7271

7374

75

i. Cbz-Clii. CrO3, AcOHiii. H2, Pd/C

R = Me, Et, ClC6H4

Nu =CO2Me

CO2Me

CO2Et

O

SO2Ph

O

CO2Me

CN

CN

CN, , , ,

Scheme 13.21


13.2.4SAAs

SAAs are defined as carbohydrates bearing at least one amino and one carboxylfunctional group directly attached to the sugar frame. Thus, such compoundsrepresent a new class of building blocks for the generation of peptide scaffolds andconstrained peptidomimetics, due to the presence of a relatively rigid furan or pyranring decorated with space-oriented substituents. Recently, Kessler et al. reported adetailed survey about the synthesis of SAAs and their applications in oligomer,peptidomimetic and carbohydrate synthesis [35]. Generally, the amino group isintroduced by azidolysis of a hydroxyl group followed by reduction and protection ofthe resulting amine, although cyanide and nitro equivalents have been also reported.The carboxylic group is usually obtained by oxidation of a primary alcohol function.Hydrolysis of cyanide or direct insertion of CO2 have been also described. Fleet et al.reported the generation of THF-templated g- and d-amino acids starting from sugar-derived lactones (Scheme13.23) [36]. The 2-triflate of the carbohydrate d-lactones (79)when treated withmethanol in the presence of either an acid or base catalyst undergoefficient ring contraction to highly substituted THF-2-carboxylates (80). Also, azideintroduction to the six-membered ring lactone, followed by subsequent SN2-type ring

CO2Et

OAcSmI2

CHOR

NHBoc THF+

HO

CO2Et

NHBoc

R

α

γ

787776

R = Bn, i-Pr, 3-Butenyl

Scheme 13.22

O

OR1

OHTfO

O

OR2O

O

R1O OH

O

OR1

N3TfO

O

OR2O

O

R1O N3

OO

R1O NH

THF templatedγ-peptides

α

γ

79

80

81

a

b

R1 = H, TBDMSR2 = Me, i-Pr

Scheme 13.23


closure of an intermediate hydroxy triflate forms the THF ring, with inversion ofconfiguration at the C-2 position. Thus, synthesis of THF-g-azido esters (81) usingthis strategy allows the introduction of the C-4 azido group either after (route a) orbefore (route b) (Scheme 13.23) formation of the THF ring.Access to bicyclic furanoid g-SAA has been reported by Kessler et al. starting from

diacetone glucose (82) and an application for solid-phase oligomer synthesis has alsobeen disclosed [37]. Specifically, azidolysis (83) gives azide (84), which, after depro-tection of the exocyclic hydroxyl groups, is subjected to azide conversion to Fmoc-protected amine (85) in a one-pot process. Final oxidation of the primary hydroxylgroup furnishes the corresponding furanoid a-hydroxy-g-amino acid (86)(Scheme 13.24).The first effective solid-phase chemical method for the preparation of carbohy-

drate-based universal pharmacophore mapping libraries was reported by Sofiaet al. [38]. The sugar scaffold (89) has three sites of diversification, with an aminoand a carboxyl group of the g-amino acid scaffold, and an additional hydroxyl group.The synthesis starts from D-glucose derivative (87) (Scheme 13.25), which is treatedwith NaIO4 and nitromethane to introduce a nitro group at C-3. Subsequentorthogonal protections, and conversion of the nitro group to the correspondingprotected amino group, gives (88), which is further oxidized to g-amino acid (89) bythe TEMPO–NaClO (TEMPO¼ 2,2,6,6-tetramethylpiperidinooxy) system. By an-choring the carboxyl group on a solid-phase, libraries of 1648 members have beenprepared using eight amino acids as acylating agents of the amino group and sixisocyanates for hydroxyl functionalization.

13.2.5Miscellaneous Approaches

An enantiopure cyclobutane-based g-amino acid was obtained from (S)-verbenone,readily available from a-pinene as a building block (Scheme 13.26) [39]. Oxidative

O

O

O

OO

RO

O

O

O

OO

N3

O

O

O

HOHO

R

O

O

O

HO

HO2C

HNFmoc

αγ

R = N385: R = NHFmoc

82: R = H83: R = Tf

Tf2O

NaN3

AcOH

1. H2,Pd/C2. Fmoc-Cl

TEMPONaClO

84

86

Scheme 13.24


cleavage of (S)-verbenone with NaIO4 in the presence of catalytic RuCl3 gave the ketoacid (90), which was esterified with benzyl chloride. The resulting ester (91) wassubjected to a haloform reaction with hypobromite to convert the methyl ketone intothe corresponding carboxylic acid,which in turnwas transformed in the amino groupvia Curtius rearrangement, giving the protected g-amino acid (92).Synthesis of polysubstituted g -amino acids of general formula (95) by rearrange-

ment of a-cyanocyclopropanone hydrates (93) to the corresponding b-cyano acid(94) was reported by Doris et al. [40]. Further reduction of the nitrile moiety ofb-cyano acid affords g-amino acid (95) with substituents in a- and b-positions(Scheme 13.27).

O OMe

OHOHHO

O OMe

NO2

OHHO

O OMe

NO2

OAc

O

OPh

O OMe

HNOAc

HO

HO

HO

OH

Fmoc

O OMe

HNOAc

HO2C

HO

Fmoc

α

γ

1.NaIO42.NaOMe,MeNO2

1.PhCH(OMe)2,H+

2.Ac2O,py1.H2,Pd(OH)2/C2.Fmoc-O-Su

TEMPO,NaClO

87

88 89

Scheme 13.25

O

O

OBn

OO

OH

O O

OBn

O

HO

BocHNO

OBnBocHN

O

OH

(S)-Verbenone

NaIO4 BnCl

K2CO3/H2O

(PhO)2P(O)N3

t-BuOH, Et3N

H2

Pd/C

90 91

92

RuCl3

NaBrO

Scheme 13.26


Sato et al. reported an efficient and practical access to enantiopure g -amino acidsusing allyl titanium complexes (97) [41]. These species are prepared by the reaction ofallylic acetal (96) with a divalent titanium reagent (h2-propene)Ti(O-iPr)2, readilygenerated in situ (Scheme 13.28), and reacts as an efficient chiral homoenolateequivalent with aldehydes, ketones and imines at the g-position [42].g -Amino acids have also beenprepared bymodification of glutamic acid [43] andby

homologation of a-amino acids. Use of a zinc reagent in straight asymmetricsynthesis of aryl g-amino acids (98) is described by Jackson et al. (Scheme 13.29) [44].Entry to bicyclic g-amino acids was proposed by Tillequin et al., who described the

synthesis of constrained scaffolds from the naturally occurring iridoid glycosideaucubin (99). The two glycosylated hydroxyl-g -amino acids (101) and (102) areprepared by chiral pool synthesis in eight steps. The amino function was introducedvia a phthalimido group, and the carboxylic function was introduced on the doublebondby formyl insertion using theVilsmeier reaction, followed by carbonyl oxidationand amine deprotectionwith hydrazine [45]. Bicyclic g-amino acid (102) was obtainedwith the same procedure as for (101) after oxidation of the double bond of (100) to an

O

O R3NC

R2R1

H2,Pd/C

AcOEtHO

HO R3NC

R2R1

HO CN

O

R1 R2

R3

[H2]HO

O

R1 R2

R3

NH2αγ

93

9495

R1 = H, MeR2 = H, Me, Et, Ph

R3 = H, Me

Scheme 13.27

O

O c-Hex

c-Hex

1. (η2-propene)Ti(O-iPr)2

R H

NBn

O

HO

c-Hex

c-HexR NHBn

+ (Z)

94 6:

R

H2N

CO2H OMeR

NBn Boc

OMeCHOR

NBn Boc

NaClO2 MeI

1. Boc2O2. Ac2O3. pTsOH,MeOH

αγ

96

2.

97

R = Me, n-Pr, i-Pr, t-Bu, Ph

Scheme 13.28


iodolactol derivative and alkaline rearrangement to the corresponding THF(Scheme 13.30).Early investigations by Seebach [4a], revealed that g-amino acid oligopeptides can

also adopt helical conformations in solution. N-Boc-protected monomers (105) havebeen prepared by homologation of L-alanine and L-valine, followed by stereoselective

ICO2H

NHBoc

1. Zn2. Pd2(dba)3

IZnCO2H

NHBoc

IR+

CO2H

NHBocR α

γ

98

R = H, 4-Me, 4-OMe, 2-OMe, 4-Br, 2-F, 4-F, 2-NO2, 3-NO2, 4-NO2, 2-NH2

Scheme 13.29

O

OH

HO H

HO-β-D-Glc

O

OPiv

N H

HO-β-D-Glc(OPiv)4

OH

H2N H

H

O

O

O

OPiv

H2N H

HO-β-D-Glc(OPiv)4

CO2H

O

CO2H

O-β-D-Glc

αγ αγ

99

102

100

101

Scheme 13.30


alkylation. Specifically, pyrrolidinones (103) are alkylated with cinnamyl bromide inthe presence of lithium bis(trimethylsilyl)amide at �78 �C, giving (104) in goodisolated yields and with high diastereoselectivities (anti : syn from 18 : 1 to 40 : 1,depending on R). Mild hydrolysis of the lactam moiety affords (105) withoutepimerization at the newly generated stereocenters (Scheme 13.31).The bicyclic pyrrolizidinone skeleton of 112 and 110 (Scheme 13.32) was obtained

by 1,3-dipolar cycloaddition of the cyclic nitrone 106 and acrylamide 107 [46]. Twomainproductswere obtained as racemicmixtures (108 and 109) and, after separation,they underwent the same synthetic route, here depicted for (�)-108 only. Thereductive cleavage/cyclization step was then followed by alcohol group transforma-tion into the target g -amino acid 112.The synthesis of enantiopure compound 112 was achieved by separation of

diastereoisomeric intermediates obtained from (�)-111 containing (1R)-1-phenyl-ethylamine as a chiral auxiliary.

NO R

BocNO R

Boc

Ph

HN CO2H

R

Boc

Ph

αγ

LiHMDS

Ph Br

LiOOH

105

103 104

R = Me, i-Pr

Scheme 13.31

O

H2N +N

MeO2C

ONO

CO2CH3

H2NOCH2O, ∆

NO

CO2CH3

H2NOC

N

CO2CH3

O

HO N

CO2CH3

O

H2NN

CO2CH3

O

H2N

107 106(+/-)-108 (+/-)-109

(+/-)-112 (+/-)-111 (+/-)-110

H2, Pd(OH)2/C

1. MsCl2. NaN33. Ni-Raney

Scheme 13.32


13.3d-Amino Acids

d-Amino acids are isosteric replacements of dipeptide units and their application inthe field of peptidomimetics has been extensively reported. In particular, since theb-turn is a common structural feature of proteins associated with the dipeptide unit,much research about d-amino acids has been concentrated on the creation of reverseturnmimetics, where the central amide bond is replaced by a rigidmoiety.Moreover,d-amino acids have been involved in the generation of new peptide nucleic acid(PNA) monomers, since the six-atom length of these amino acid homologs corre-sponds to the optimal distance to mimic the ribose unit found in RNA and DNApolymers. Relevant examples of d-amino acids include linear, cyclic, bicyclic andspiro compounds, and different templates have been applied for the generation ofsuch amino acids.

13.3.1SAAs

d-Amino acids of the SAA class have been synthesized as furanoid or pyranoidcompounds, andboth cyclic andbicyclic scaffoldshavebeenreported (Scheme13.33).

13.3.1.1 Furanoid d-SAAAmong furanoid d-SAA, either monocyclic compounds or oxabicyclo[3.3.0]octaneand oxabicyclo[3.2.0]heptane structures have been synthesized by several authorsaccording to different synthetic routes shown in Scheme 13.34.Furanoid d-SAA (115) and (117) have been obtained using different strategical

approaches by three different authors: Le Merrer et al., Chakraborty et al., and Fleetet al., as reviewed by Kessler et al. [35]. Le Merrer et al. used mannose as startingmaterial to generate the enantiomerically pure double epoxide (113) [47], which wastreated with NaN3 and silica gel to generate the corresponding azidomethyl-furanoidsugar (114). Oxidation of primary hydroxyl group, and conversion of the azido groupto Boc-protected amine produces the furanoid d-SAA (115). Starting from theenantiomeric epoxide (116), also obtained from D-mannitol in six steps, it is possibleto achieve the synthesis of the d-amino acid (117) having the same orientation offunctional groups relative to the ring, but inverted configurations of the amino andcarboxylic functions at the C-1 and C-5 positions, respectively (Scheme 13.35).Chakraborty et al.�s approach consists of an intramolecular 5-exo ring-opening of

a terminal N-Boc-aziridine [48], derived from a-glucopyranose, during alcohol to

OOH2N CO2H H2N CO2H

furanoid-δ-SAA pyranoid-δ-SAA

Scheme 13.33

13.3 d-Amino Acids j547

acid oxidation, resulting in the protected furanoid d-SAA (119) similar to (115) withcomplete stereocontrol (Scheme 13.36). The stereoisomerically pure aziridine (118)obtained from the same treatment from the D-mannose precursor generates thecorresponding isomeric d-amino acid (120), having the configuration at C-1inverted.Fleet et al. reported a range of stereoisomeric furanoid d-SAA starting from sugar-

derived lactones [49]. For example, the previously described compound (119) wasobtained as the azido ester (123) from D-mannono-g -lactone (121) by acid-catalyzedring rearrangement of the corresponding triflate (122) (Scheme 13.37).More recently, the same authors reported the synthesis of all diastereomeric

precursors to THF-templated d-amino acids lacking the hydroxyl at C-2, startingfrom mannono- and gulono-lactones [50], in analogy with the corresponding THF-templated g-amino acids (Scheme 13.38) [36]. Two different strategic approaches

O CO2H

RO OR'

H2NO CO2H

RO

H2NO CO2H

H2N

O CO2HH2N

OO

O

O

O

SR

H2N

HO2C

O CO2H

O OH

H2N

OHO2C

O OH

NH2

monocyclic

[3.3.0]

[3.2.0]

Scheme 13.34

D-Mannitol

O

BnO OBn

N3HOOMeO2C

BnO OBn

NHBoc

O

BnO OBn

N3HO

OMeO2C

BnO OBn

NHBocα δ

α δ

113 114 115

117116

4 step

six steps

NaN3

NaN3

2.H2,Pd/C3.Boc2O

OBn

OBn

O

O

OBnO

O

1.Na2Cr2O7then CH2N2

OBn

1.Na2Cr2O7then CH2N2

2.H2,Pd/C3.Boc2O

Scheme 13.35


have been proposed, by changing the order of deoxygenation and THF formationreactions.The hydroxylated THF-carboxylic acid derivatives have been further manipulated

to obtain the azido esters as d-amino acid precursors: selective activation of primaryhydroxyl group with tosyl chloride was followed by azide insertion at the d-position.Recently, a set of conformationally locked d-amino acids have been proposed,

based on furan rings [51]. In particular, a bicyclic furano-oxetane core has beenproposed as scaffold for a constrained d-amino acid. The synthetic strategy is basedupon CO insertion on fully protected b-D-ribofuranoside (124), followed by conver-sion of a primary alcohol function at C-1 to azide to give (125). After hydroxyl group

O CO2H

HO OH

BocHN

O OMe

OBnOBn

BnO

N3O OH

OBnOBn

BnO

N3OH

N3

OH

OBn OBn

OBn

OHOBn OBn

OBnN

R

118: R = H R = Boc

α-glucopyranosederivative

O CO2H

HO OH

BocHN

D-mannose derivative

δα

δα

119

120

HCl NaBH4

MeOH

Ph3P

Boc2O

PDC,DMF

Scheme 13.36

O

OHHO

CO2MeHO

O

OHHO

CO2MeN3

D-mannono-γ-lactone

OO

O

OHHO

OO

O

O

OHTfO

O

δ α

Tf2O

HClMeOH

1. TsCl2. NaN3

121122

123

Scheme 13.37


protection/deprotection steps, oxidation of primary alcohol group, followed by aldolcondensation with formaldehyde and oxetane cyclization step produces (126), whichis treated with Boc-on and Me3P to convert the azido group into the correspondingBoc-protected d-amino acid (127) (Scheme 13.39).Inversion of functional groups to obtain the isomeric d-amino acid (129) was

accomplished by protection of the alcohol function at C-1 of (128) as the tert-

O

O

OO

OHHO

O

O

OO

HO

OOH

OHHO

MeO2C

OOH

OH

MeO2C

deoxygenation

deoxygenationTHF formation

THF formation

Scheme 13.38

O OAc

BzO OBz

O

BzO OBz

OHO

RO OR

N3

ON3

OO

ON3

OO

BzO BzO BzO

HOO

125: R = Bz R = H

HO

N3

OO

RO

RO

R = HR = Ms

ON3

OHHO

MsO

MsO

O

O

RO

OH

N3O

O

HO2C

OH

NH

Boc

126: R = MsR = H

1. MsCl2. NaN3

t-BuOKMeOH

2,2-dimethoxy-propane

Dess-Martin1. CH2O2. NaBH4

MsCl

HCl

NaOH

HCl

1. Boc-on, Me3P2. TEMPO, NaClO

αδ

124

127

CO

Co2(CO)8

Scheme 13.39


butyldiphenylsilyl ether, followed by conversion of C-5 to a Boc-protected aminogroup via azide formation (Scheme 13.40).The conformational rigidity of the pyran and furan rings makes carbohydrate-

derived amino acids interesting building blocks for the introduction of specificsecondary structures in peptides. For example, compound 132 (Scheme 13.41) wasincorporated into the cyclic peptide containing the RGD (Arg–Gly–Asp) loopsequence by solid-phase peptide synthesis using Fmoc chemistry [52]. Reductionof the azide to amine group and coupling with the desired amino acid was realized inone pot in the presence of Bu3P and carboxylic acid activating agents. Allyl com-pounds 130, derived from allylation of 2,3,5-tri-O-benzyl-D-arabinofuranose, under-went iodocyclization to 131 as a diastereomeric mixture, easily separated by chro-matography. This step, crucial for the formation of bicyclic scaffolds, consisted of anintermediate iodonium ion opening by attack of the g-benzyloxy group and formationof a cyclic iodoether with simultaneous debenzylation. The final azido acid 132 wasobtained by reaction with Bu4NN3, followed by selective deprotection steps andprimary alcohol Jones oxidation.

O

BzO OBz

OHBzO

OOTBDPSHO

OOTBDPS

OO

RO

RO

R = HR = Ms

OO

OOTBDPS

O OH

MsOO

O

BocHN

OH

OH

O

O

BocHN

OH

CO2H

128

1. TBDPS-Cl2. t-BuOK, MeOH

OMeMeO

3.3. NaBH4

MsCl

1. FeCl3 2. NaOH

3. TBAF

TEMPONaClO

αδ

129

, PTSA

1. Dess-Martin2. CH2O

1. NaN32. Boc-on, PMe3

Scheme 13.40

O

OBnO

HO2CN3

H

H

O

OBnBnO

BnO

O

OBnO

IH

HBnO

I2

i.Bu4NN3ii.Ac2Oiii.MeONaiv.Jones

130 131

132

Scheme 13.41


13.3.1.2 Pyranoid d-SAAd-Amino acids belonging to the SAA class constrain a linear peptide chain whenthe NH2 and COOH groups are in the 1,4-positions. In particular, such d-SAAshave been thought of as rigidified D-Ser–D-Ser dipeptide isosteres, as shown inScheme 13.42 [53]. The synthesis of b-anomer 133 has been reported starting fromglucosamine.Ichikawa et al. reported the synthesis and incorporation in oligomeric structures of

a series of glycamino acids, a family of SAAs that possesses a carboxyl group at theC-1position and the amino group at C-2, -3, -4, or -6 position [54]. In particular, d-aminoacids with the amino group in position 4 or 6 have been reported, and the synthesesare shown in Schemes 13.43 and 13.44. Benzylidene-protected ester (135) is obtainedstarting from methyl b-D-galactopyranosyl-C-carboxylate (134) by treatment withbenzaldehyde and formic acid. O-Benzylation and reductive opening of the benzy-lidene group are followed by treatment with Tf2O andNaN3, to give the Boc-protectedamino group at C-4 position after reduction and protection of the azido derivative(136). Oligomerization has been carried out using deprotected hydroxyl functions ofBoc-protected d-amino acid (137).The synthesis of d-amino acid (139) was accomplished starting from D-glucose,

using an aldol reaction to introduce a nitromethylene group at the anomeric positionof (138) as an aminomethylene equivalent, followed by selective oxidation of theprimary hydroxyl group to a carboxylic acid (Scheme 13.44) [55].As an alternative approach to pyranosidic glucose-derived d-amino acids, Xie et al.

proposed a synthetic route from b-C-1-vinyl glucose to generate d-SAA

AcBr1. MeOH,Py 2.Cbz-Cl

MeOHMe2EtN

Pt/C

O2

O OH

NH3+Cl-HO

OH

OH

O Br

NH3+Br-AcO

OAc

OAcO OMe

NHCbzAcOOAc

OAc

O OMe

NHCbzHOOH

OHO OMe

NHCbzHOOH

HO2C α

δ

OCO2H

HO

H3CO

H2N

OH

NHHN

O

OHO OH

D-Ser-D-Ser Sugar δ-aa

D-glucosamine

133

Scheme 13.42


(Scheme 13.45) [56]. Starting from vinyl-glucoside (140), selective deprotection of6-benzyloxy group affords (141). Primary alcohol oxidation with pyridinium chlor-ochromate leads to (143), which is treated with O3/NaBH4 as an oxidation–reductionstep to insert a hydroxymethyl function at C-1. Final activation and azide insertionproduces the d-amino acid precursor (144). Alternatively, azide insertion at C-6 viamesylation of hydroxymethyl group followed by treatment with NaN3 allows thesynthesis of the d-amino acid precursor (142), thus inverting the order of reactions.Oligomerization has been carried out in solution using the corresponding azido esterand protected amino acid for subsequent coupling reactions.Pyranoid d-amino acids have also been described by Sofia et al. for solid-phase

generation of carbohydrate-based universal pharmacophore mapping libraries [38].The sugar scaffold is providedwith three sites of diversification, using an amino and a

O CO2Me

OHHO OH

HO O CO2Me

OHOH

O

O

O CO2Me

OBnOBn

BnO

R

136: R = N3 R = NHBoc

O CO2H

OHOH

HO

NH

Boc

PhCHO

1. NaH, BnBr2. NaBH3CN, HCl3. Tf2O4. NaN3

1. H2S2. Boc2O

1. H2, Pd(OH)2/C2. LiOH, MeOH

α

δ

Ph

134 135

137

Scheme 13.43 d-Amino acid monomer for b-1–4-linked oligomers.

O OH

OH

HO

OHHO

O

OH

HO

OHHO

NO2

O

OH

HO

OHHO

N

H

FmocO

OH

HO2C

OHHO

N

H

Fmocα δ

CH3NO

2

1. H2, Pd/C

2. Fmoc-Cl

TEMPO

NaClO

D-glucose 138

139

Scheme 13.44


carboxyl group of the d-amino acid scaffold, and an additional hydroxyl group. Thesynthesis of selected d-amino acid scaffolds was achieved starting from glucosamineby amine protection as Cbz-urethane, followed by treatment with 2,2-dimethoxy-propane to protect hydroxyl groups at C-5 and C-6. Methylation of the hydroxyl at C-4afforded the orthogonally protected (145). Subsequent oxidation with TEMPO–Na-ClO of the deprotected primary hydroxylic function, hydrogenation and Fmocprotection, and gave the d-amino acid (146) with a free hydroxyl at C-4(Scheme 13.46).

13.3.2d-Amino Acids as Reverse Turn Mimetics

Among d-amino acids as reverse turn inducers, a classification can be madedepending upon their structural features. In particular, linear, cyclic, and bicycliccompounds have been developed as dipeptide isosteres and reverse turn inducers.Recently, an overview of all the possible folding alternatives of d-amino acids inoligomeric d-peptides with respect to the parent a-peptides was reported usingvarious methods of an ab initio molecular orbital theory [57]. In particular, cyclicd-amino acids have been investigated as possible reverse turnmimetics, showing thestrict relationship between stereochemistry on the ring system and secondarystructure of the sequence containing the d-amino acid. An early example of a lineard-amino acid as a reverse turn inducer was first reported by Gellman et al. [58], inwhich a trans C¼C double bond was introduced to replace the amide bond of the

O

OBnBnO OBn

BnO O

OBnBnO OBn

HOO

OBn

ButO2C

BnO OBn

O

OBnBnO OBn

N3O

OBn

ButO2C

BnO OBn

OH

O

OBn

ButO2C

BnO OBn

N3

O

OBnBnO OBn

N3 OH

O CO2tBu

OBnBnO OBn

N3αδ α

δ

1.TMSOTf, Ac2O2.NaOMe,MeOH

PCC, Ac2OROH

1.O32.NaBH4

1.MsCl2.NaN3

1.MsCl2.NaN3

1.O32.NaBH4

PCC, Ac2Ot-BuOH

140 141 143

142 144

Scheme 13.45


central dipeptide of the b-turn. Thus, such alkene-based b-turn mimetics have beenthought of as rigidified mimetics of a Gly–Gly dipeptide (Scheme 13.47).Other authors reported the synthesis and conformational analysis of alkene-based

dipeptide isosteres in which the d-amino acid is substituted in the a- and d-positionswith methyl groups [59]. The synthetic strategies allow one to obtain d-amino acid(147) in diastereomerically and enantiomerically pure form as a D-Ala–L-Ala isosterevia SN20 addition of cuprate reagents to the alkenyl aziridine (148) (Scheme 13.48).

O OH

NH3+Cl-HO

OH

HOO OCH3

NH

HOOH

HO

O OCH3

NH

OCH3

O

O

O OCH3

NH

OCH3

HO2C

HO

O OCH3

NH

OCH3

HO2C

HO

Cbz

Cbz

Cbz Fmoc

α

δ

1.Cbz-Cl2.MeOH,HCl

OMeMeO1.

2.NaH,CH3I1.pTsOH2.TEMPO,NaClO

1.H2,Pd/C2.Fmoc-Cl

D-glucosamine

145

146

Scheme 13.46

OOH

HNCO2MeN

H

Boc CO2Me

D-Ala-L-Ala isostere

147 148

Scheme 13.48

NH

NH

OOα

βγ

δ N

OHN

O

NOO

N

H

H

Scheme 13.47


Many of the bicyclic d-amino acids have been designed as dipeptide mimeticreplacements of the i þ 1 and i þ 2 residues in b-turn systems. For this reason,attempts to correctly positioning the N- and C-termini of the dipeptidomimetic unitresulted in an obligatory d-amino acid, often incorporating an amide bond in thebicyclic backbone (Scheme 13.49).The most common approach to substitute the central dipeptidic sequence of

b-turns with peptidomimetics has been to use tethered prolines within bicyclicscaffolds, since such amino acid are often found inb-turns, especially in types I and IIin the i þ 1 position, and in type VI in the i þ 2 position, the last having the amidebond in a cis configuration. Most syntheses focused on proline-based bicyclic d-amino acids, can be divided into numerous azabicyclo[x.3.0]alkane subclasses (seeScheme 13.50 for a few examples).In most cases the key step of the synthesis is the lactam ring formation that can be

obtained by different approaches (Scheme 13.51) [60, 61]: the radical addition to anolefinic double bond, alkylation of malonate enolate, ring-closing metathesis, intra-molecular alkylation followed by amidation and Hoffman rearrangement, and aldolcondensation [62]. Further functional groups at the a-position could be inserted onthe final scaffold by alkylation under basic conditions [63].More generally, Lubell et al. reported an extensive overview on tethered prolines to

generate bicyclic compounds of general formula as shown in Scheme 13.52. Inparticular, a systematic description of synthetic procedures leading to different sizedbicycles having additional heteroatoms is reported [64]. The introduction of sub-stituents on both cycles to mimic the side-chain of the central dipeptide of b-turns isalso described.Other examples include the generation of 3-aminooxazolidino-2-piperidones as

Ala–Pro dipeptide surrogates, and conformational analysis to demonstrate the type

NH2N

O CO2H

HN

O N

O

Ri+1

NH

ORi+2

generic β -turn

N ORi+3Ri

H

H

αδ Y

X Z

α δ

mn

generic bicyclic δ -amino acid

Scheme 13.49

N N

O

N

O ORHN

RHN

CO2H CO2H CO2H

R1

R1

R2 R2

R3

RHN

[3.3.0] [4.3.0] [5.3.0]

Scheme 13.50


II0 b-turn inducing properties of such d-amino acids (Scheme 13.53) [65]. Compound(150) was obtained in a one-pot process from the glutamic acid-derived aldehyde(149) andSer-OMe. Structural analysis of the end-protected compound (151) revealedthe all-(S) stereoisomer to act as the best reverse turn mimetic.Bicycles constituted by six- and five-membered rings have been used as type VI

b-turn mimetic and antiparallel b-ladder nucleators [66]. Bicyclic scaffold (152)derives from proline and carries the carboxylic function at the bridgehead position(Scheme 13.54). Detailed conformational analysis revealed its peculiar reverse turnproperties.

N CO2tBu

Cbz

n N

O CO2tBu

NH

nCbzHN

MeO2C

N CO2tBu

HOn

OR

CO2Me

R

N CO2tBu

n

O

NHCbzR

A B

C

Cbz

R = H, Bn

Scheme 13.51

N

Y

OH2N

CO2H

R2R1

αδ

Scheme 13.52

N

O

O

H

NH CO2Me

CbzN

O

CHOCbzSer-OMe

N

O

O

H

HN

OOO

HNBn

αδ

149 150

151

O

Scheme 13.53


Two approaches (i.e., radical and nonradical) have been investigated by Scolasticoet al. to accomplish lactam ring formation [60]. Radical cyclization involves radicaladdition to an olefinic double bond, and, among nonradical methods, alkylation ofmalonate enolate, ring-closing metathesis, and lactam bond formation have beentaken into account (Scheme 13.55).Detailed conformational analysis by nuclear magnetic resonance, infrared, and

molecular modeling techniques [67], as well as applications as thrombin inhibi-tors [68], and in RGD-based cyclopeptides such as avb3-integrin ligands [69], provedthis class of compounds to act as d-amino acid reverse turn mimetics.A recent example of a spiro-b-lactam system was obtained via Staudinger reaction

of the disubstituted ketene (153) deriving from Cbz-proline, giving a reverse turnmimetic by reactionwith a glycine-derived imine [70].Compound (154) as depicted inScheme 13.56 was obtained exclusively as a consequence of cis stereoselectivity of theprocess. Such a compound is designed using high-level ab initio methods, andconformational analysis via nuclear magnetic resonance demonstrated the scaffoldstabilized a b-turn conformation with a geometry close to an ideal type II b-turn, byrestricting the f and j torsion angles in the i þ 1 position.Extremely constrained spiro-bicyclic lactams of 5.6.5 and 5.5.6 size, as shown in

Scheme 13.57, have been investigated as PLG (Pro–Leu–Gly) peptidomimetics forthe modulation of dopamine receptor activity [71]. An earlier report by the sameauthors described the generation of the corresponding 5.5.5-sized scaffold [72].

N

BnO2C

NHBoc

ON NH

O

NHOO

O

HN

R2

R1

αδ

152

R1 = H, CH2PhR2 = H, CH2Ph

Scheme 13.54

N N

N

O

O

O CO2H CO2H

CO2H

R2

R2

R2

R1

NH

NHR1

NHR1

[3.2.0] [4.2.0]

[5.2.0]

αδ

αδ

αδ

R1 = H, BnR2 = H, Me

CbzCbz

Cbz

Scheme 13.55


Structural analysis by X-ray and computational methods revealed these compoundstomimic a type IIb-turn, and a strong dependence of torsion angleswith ring size hasbeen evidenced.The synthetic strategy to produce the 5.5.6 scaffold consists of stereoselective allyl

alkylation of proline followed by protection of the amino and carboxylic functions.Double-bond oxidative cleavage of (155) with OsO4/NaIO4 followed by condensationwith homocysteine produces the thiazinane (156). Direct intramolecular amide bondformation generates the title fully protected d-amino acid (157) after esterification ofthe carboxylic function with diazomethane (Scheme 13.58).The synthesis of spiro bicyclic d-amino acid (161) starts with alkylation of proline-

derived oxazolidinone (158) with 4-bromo-1-butene (Scheme 13.59). Subsequentlactone ring opening, protection of amino and carboxylic functions, and double-bondoxidative cleavage produces aldehyde (159), which was condensed with cysteine,and the resulting adduct (160) was allowed to cyclize to furnish the 5.6.5 d-aminoacid (161).Another example of a bicyclic structure bearing a pyrrolidine ring was reported by

Johnson et al., which used 2-allylproline to generate a 4,4-spirolactam scaffold as atype II b-turnmimetic [73]. d-Valerolactam has been used to generate a lactam-basedd-amino acid as reverse turn mimetic [74]. In particular, diversity in the six-membered ring of compound (162) is obtained by conjugate addition on the doublebond, followed by Curtius rearrangement to introduce the amino group(Scheme 13.60).

NCl

O

CbzN C

Cbz

ON

NCbz

O

Ph

CO2Me

N CO2MePh

NN

OHNO

O

Ph

NHBoc

type II β-turn

α

δ

153 154

Et3N

Scheme 13.56

N

S

N

O OOH2NNH

N

S

ON

O H2NO

NH 5.6.5 5.5.6

αδαδ

Scheme 13.57


A unique example of a macrocyclic d-amino acid as a reverse turn mimetic wasreported in 1998 (Scheme 13.61). Katzenellenbogen et al. described the synthesis of a10-membered ring as a type I b-turn mimetic by dimerization of the a-amino acid2-amino-hexenoic acid (163), followed by ring-closing metathesis of the resultingadduct (164) [75].The class of bicyclo[x.y.1] g/d-amino acid scaffolds is mainly represented by 6,8-

dioxa-3-azabicyclo[3.2.1]octane-7-carboxylic acids (165) named BTAa (Bicycles fromTartaric acid and Amino acid; Scheme 13.62) [76], easily synthesized from thecondensation of a-amino aldehyde derivatives (166) with tartaric acid (167) or sugarderivatives in a stereoselective fashion [77]. The insertion of 6,8-dioxa-3-azabicyclo[3.2.1]octane-7-carboxylic acids in cyclic and linear peptidic sequences demonstratesthe ability of these scaffolds to revert a peptide chain.Phenylalanine-derived amino alcohol (168) was coupledwith L-tartaric acidmonoes-

ter derivative (169) to give the corresponding amide (170), which was successivelyoxidizedat theprimaryhydroxyl groupandcyclized inrefluxing toluene in thepresence

N CO2MeBoc

N CO2Me

CHO

Boc

N CO2Me

Boc

NHS

CO2H

N

S

N

O CO2MeBoc α

δ

155

156157

OsO4,NaIO4

HomoCys

1.TEA,70°C2.CH2N2

Scheme 13.58

NO

ON

O

ONBoc

CO2H

NBoc

CO2BnNBoc

CO2Bn

NHS

CO2Me

N

S

CO2MeONBoc

5.6.5

αδ

CHO

158

159160161

Br

BuLi 1. SiO2, MeOH-H2O

OsO4,NaIO4

2.D-Cys-OMe

NMe

Cl+I- 1.H2,Pd/C

2. (CH3)4N+OH-, Boc2O, AcCN

Scheme 13.59


ofacidsilicagel.Furthermanipulationsof (171) tothecorrespondingd-aminoacid(172)consists of complete LiAlH4 reduction, N-debenzylation, Fmoc protection, and finaloxidation using Jones� methodology with CrO3–H2SO4 (Scheme 13.63).In particular, if C-7 has an endo configuration, a dipeptide isostere reverse turn

mimetic can be obtained, which can mimic the central portion i þ 1 – i þ 2 of acommon b-turn (Scheme 13.64).The first example was the introduction of a 7-endo-BTAa in a cyclic Bowman–Birk

inhibitorpeptideasanIle–Promimetic, showing that thescaffold isable tomaintain theexisting turn [78]. Successively, a detailed conformational analysis on linear modelpeptides containing leucine-derived BTAa demonstrated the reverse turn inducingproperties of these bicyclic g/d-amino acids and the effect of substituentd-position [79].

NO

BnO2C

CO2tBu

δ-ValerolactamNO

BnO2C

CO2tBu

R

NO

FmocHN

CO2tBu

R

N

R

OHN

O HNO

α

δ

162

1.LiHMDS,ClCO2Bn,PhSeCl2.mCPBA RMgBr

1.DPPA2.Dibutyltin dilaurate,BnOH3.H2,Pd/C, then Fmoc-O-Su

R = 3-Indole, Et, Ph, CN

Scheme 13.60

NN

OCH3

OCH3

BrN

N

OCH3

OCH3

BocHN

CO2Me

BocHN

CO2H

H2N

CO2Me

NH

ONHBoc

RO2C

NH

ONHBoc

HO2C NH

O

NHO

NHO

α δ

163

164

BuLi

1.HCl2.Boc2O3.AgNO3

HCl NaOH

PyBOP

Grubbs' RCM

Scheme 13.61


13.3.3d-Amino Acids for PNA Design

In 1991, Nielsen et al. reported the synthesis and properties of new DNA analogsbased on complete substitution of the DNA backbone with a polyamidic chaincovalently linked to the DNA nucleobases [80]. Most of PNA monomers have beendesigned according to a �golden rule�: the number of atoms of the repeating unit in

ON O

CO2HFmoc

δ

γ

NH

OBn MeO2CCO2Me

OH

OH

+

tartaric acid derivative

α-amino aldehydederivative

R1

R1

ON O

CO2MeBn

R1

O 17

5

α

δ

H

165

167166

R1 = H, Me, Bn, CH2OBn, n-Butyl

Scheme 13.62

BnNH

OH+

OO

CO2MeHO2C

BnN

OH

O

O O

CO2Me

BnN CHO

O

O O

CO2MeO

NBnCO2Me

O

O

ONFmoc

CO2H

O α

δ

γ

PyBrOP

(COCl)2-DMSO

SiO2,H2SO4

1.LiAlH42.H2,Pd(OH)2/C3.Fmoc-O-Su4.CrO3,H2SO4

168 169 170

171172

1

45

7

Scheme 13.63


the polyamide chain should be six and the number of atoms between the backboneand the nucleobase (B) should be two, as shown in Scheme 13.65 [81].Various examples of PNAmonomers have beenproposed to satisfy the golden rule,

and to provide a switch towards selectivity in the complexation with DNA and RNA.Introduction of constraints by means of five- or six-membered ring structures in theaminoethylglycyl-PNA contributes to reducing the entropic loss during complexformation, and maintains a balance between rigidity and flexibility in the backbone.Pyrrolidine and pyrrolidone rings have been selected as scaffolds for cyclic PNAmonomers since the nitrogen atom of the ring serves as the amino group forbackbone or side-chain conjugation with purinyl- or pyrimidinyl-acetic acid deriva-tives. In particular, 4-OH-proline has become the most popular starting material togenerate such PNA monomers (Scheme 13.66).Compounds (173), (174), (175), and (176) derive from 4-OH-proline, while

compound (177) shows a thiazolidine ring. In compound (173), the hydroxy groupat position 4 of the starting amino acid is used to insert the base via Mitsunobureaction. Thus, the pyrrolidine ring of the resulting PNAmonomer is thought of as aconstraint of the b,g -positions, with the side-chain containing the nucleobase [82].The synthesis is shown in Scheme 13.67 starting fromBoc-4-OH-proline. The aminogroup is inserted in position 5 of the ring via ester reduction of (178), followed byazide introduction in (179). The carboxylic group is inserted in (180) by reaction ofpyrrolidine nitrogen atom with methyl a-bromoacetate, and after azide reduction-amine protection, the resulting Boc-d-amino acid (181) was obtained, and succes-

N

O

O

HNO

OHN

NH

HN

O

O

R1 R2

O

RH

generic β-turn endo-BTAa

R1 = R2 = aa side chainR = Me, Bu, s-Butyl

Scheme 13.64

OOP

OP

B

12

345

6

III

N

OB

H2N

CO2H

1

23

45

6

III

nucleoside aeg-PNA

N

OB

H2N

CO2H

δ-amino acid

α

δ

P = phosphate groupB = A, C, G, T

Scheme 13.65


sively transformed in the PNAmonomer (182) by means of 4-hydroxyl deprotection-activation and nucleobase insertion.Six-membered ring PNA monomers have been developed using mainly cyclohex-

ane or pyranosidic sugars as scaffolds. Cyclohexane decorated with the amino,carboxyl, and base groups on the cycle has been synthesized starting from butadienevia enantioselective cycloadditionwith acryloyl-oxazolidinone (183) in the presence ofTADDOL (4,5-bis[hydroxy(diphenyl)methyl]-2,2-dimethyl-1,3-dioxolane) as chiralcatalyst (Scheme13.68) [83]. Nucleobase insertionwas accomplished via nucleophilicsubstitution reaction on the bicyclic species (184), which gives the title d-amino acid(185) after final ring opening.

13.3.4Miscellaneous Examples

Similar to the work by Smrcina et al. [31], b-amino acids have been used to generatefunctionalized d-amino acids. In particular, it is reported by Guichard et al. atsynthesis of a,d-disubstituted d-amino acids (189) starting from b-amino acids(186), through the generation of d-valerolactam (187), which are successively alky-lated and opened to give the corresponding linear d-amino acid (189) [84]. As shownin Scheme 13.69, the valerolactam ring is generated from the b-amino acid byreaction with Meldrum�s acid, followed by carbonyl reduction and cyclization.Enolate alkylation at C-3 of (187) to give (188) is trans stereoselective with respectto the side-chain functional group of the starting b-amino acid.The morpholine nucleus has been recently used as a scaffold to generate d- and

e-amino acids starting from carbohydrates (Scheme 13.70) [85]. The syntheticstrategy relies on a two-step glycol cleavage/reductive amination process, to givethe morpholine-based amino acid. In order to obtain such d-amino acids, ribose waschosen as the starting carbohydrate and transformed into the corresponding unpro-tected methyl azido ester derivative (190) [86].

N

B

BocHN

CO2Meα

δ

N

H2N

B

CO2Me

N

B

CO2H

ONH2

N

H2N

CO2H

OB

S

N

OB

CO2HH2N

N

B

NH2

CO2H

O

NH

N CO2HO

B

αδ

α

δ

α

δ

αδ

αδ

174173

177176175

B = Nucleo base

Scheme 13.66


N

OH

RO2C

Boc

R = HR = Me

N

OTBDMS

MeO2C

BocN

OTBDMS

Boc

RO

R = HR = Ms

N

OTBDMS

Boc

N3

NH

OTBDMS

N3N

OTBDMS

N3

CO2Me

N

OTBDMS

BocHN

CO2Me

N

OR

BocHN

CO2Me

R = HR = Ts

N

B

BocHN

CO2Meα

δ

178

179180

181 182

Cs2CO3,MeI

TBDMS-Cl LiBH4

MsCl

NaN3

TFABrCH2CO2Me

H2,Pd/C,Boc2O

TBAF

TsCl

base

Rapoport's reagent

B = Adenine

Scheme 13.67

O

N O

O

+

O

N O

O O

OR

R = H, Me

OHR

R = OMsR = CN

O

NH2

HN

O

I

HN

O

B

BNHBocRO2C α δ

183

184 185

cat.TADDOL Mg,MeOH

LiAlH4

MsCl

NaCN

Cu,H2O

1.TMSOTf2.I2

NaH

Nuceo base

B = A,T

Scheme 13.68


Unavoidable epimerization during glycol cleavage forced the authors to devise anew strategy to avoid an undesired b-keto ester. Thus, starting from either (193) or(196), respectively, stereoisomeric d-azido esters (194) and (197) have been achievedas amino acid precursors of the corresponding (195) and (198) (Scheme 13.71).

13.4Conclusions

The possibility of having a broad spectrum of g- and d-amino acids, either linearor cyclic, allows the generation of different species able to interact with biological

NH

CO2HR1

Boc NH

R1

Boc

O

O

O O

O

NH

R1

Boc

O

O

O

O

N OBoc

R1N OBoc

R1

R2

BocNH

CO2HR1

R2

EDCI

Meldrum'sacid

toluene,110°C

R2X

base

LiOHαδ

NaBH4

186

187188189

R1 = Me, n-Bu, s-BuR2 = Me, n-Bu, CH2=CHCH2, CH2=C(CH3)CH2, (CH3)2CHCH2

X = Br, I

Scheme 13.69

O OH

HO OH

HO O CO2MeN3

OO

O CO2Me

HO OH

N3

N

O CO2CH3

Bn

N3

N

O CO2CH3

Bn

N3

+

D-Ribose

αδαδ

190192191

ref. [86]

HCl,MeOH

1.H5IO62.(MeO)3CHNaBH3CN,BnNH2

Scheme 13.70


systems. In particular, the high tendency of such new amino acids to fold intostable secondary structures enables their application in oligomer synthesis ofmore complex structures. g -Amino acids are particularly relevant in the contextof lead development, since they allow presentation of different functional groupsin a relatively compact structure, either linear or cyclic in nature. Thus, mucheffort has been dedicated to the development of asymmetric synthetic strategiesto obtain g-amino acids with high stereocontrol. Moreover, interest in the field ofmedicinal chemistry related to the design of GABA and statine analogs is everincreasing. d-Amino acids have been reported to play a central role in the designof peptidomimetics, especially in the field of b-turn analogs. Sugar amino acid-based scaffolds gathered interest in both oligomer synthesis and peptidomimeticsdue to the attractive feature of presenting many functional groups anchored ina rigid scaffold in well-defined positions. Moreover, research in the field ofPNAs turned much attention towards both linear and cyclic enantiopure d-aminoacids for developing new PNA strands with increased selectivity with respectto complex formation with RNA and DNA. Thus, research in the field of g- andd-amino acids is ever active in diverse fields of medicinal chemistry, span-ning from peptide-based drug design to oligomer synthesis, and also in thedevelopment of new efficient synthetic methods for g- and d-amino acid-basedcompounds.

O

O

O

HO

N3O

N3

OHHO

OH

N

O

Bn

N3 OH

191

O

OH

OH

HO

HOO

OH

OH

HO

N3

N

O

Bn

N3

192

OH

194193 195

196 197 198

TFA,MeOH

1.H5IO62.(OMe)3CH,NaBH3CN,BnNH2

TEMPOBAIB

TEMPOBAIB

1.H5IO62.(OMe)3CH,NaBH3CN,BnNH2

1.MsCl2.NaN3

Scheme 13.71

References

1 (a) Giannis, A. and Kolter, T. (1993)Angewandte Chemie (International Editionin English), 32, 1244; (b) Gante, J. (1994)Angewandte Chemie (International Editionin English), 33, 1699.

2 (a) Abdel-Magid, A.F., Cohen, J.H., andMaryanoff, C.A. (1999) Current MedicinalChemistry, 6, 955; (b) Juaristi, E. and Lopez-Ruiz, H. (1999) Current MedicinalChemistry, 6, 983; (c) Sewald, N. (1996)

References j567

Amino Acids, 11, 397; (d) Cole, D.C. (1994)Tetrahedron, 50, 9517.

3 (a) Gellman, S.H. (1998) Accounts ofChemical Research, 31, 173; (b) Iverson,B.L. (1997) Nature, 385, 113; (c) Seebach,D. and Matthews, J.L. (1997) Journal of theChemical Society, ChemicalCommunications, 2015.

4 (a) Hanessian, S., Luo, X., Schaum, R., andMichnick, S. (1998) Journal of the AmericanChemical Society, 120, 8569;(b) Hintermann, T., Gademann, K., Jaun,B., and Seebach, D. (1998) HelveticaChimica Acta, 81, 983.

5 Szabo, L., Smith, B.L., McReynolds, K.D.,Parrill, A.L., Morris, E.R., and Gervay, J.(1998) The Journal of Organic Chemistry,63, 1074.

6 (a) Duke, R.K., Chebib, M., Hibbs, D.E.,Mewett, K.N., and Johnston, G.A.R. (2004)Tetrahedron:Asymmetry, 15, 1745; (b)Allan,R.D., Bates, M.C., Drew, C.A., Duke, R.K.,Hambley, T.W., Johnston, G.A.R., Mewett,K.N., and Spence, I. (1990) Tetrahedron,46, 2511.

7 (a) Hoveyda, A.H., Evans, D.A., and Fu,G.C. (1993) Chemical Reviews, 93, 1307;(b) Evans, D.A., Gage, J.R., Leighton, J.L.,andKim,A.S. (1992)The Journal ofOrganicChemistry, 57, 1961; (c) Belliotti, T.R.,Capiris, T., Ekhato, I.V., Kinsora, J.J., Field,M.J., Heffner, T.G., Meltzer, L.T., Schwarz,J.B., Taylor, C.P., Thorpe, A.J., Vartanian,M.G., Wise, L.D., Ti, Z.-S., Weber, M.L.,and Wustrow, D.J. (2005) Journal ofMedicinal Chemistry, 48, 2294; (d) Brenner,M. and Seebach, D. (1999) HelveticaChimica Acta, 82, 2365; (e) Yuen, P.-W.,Kanter, G.D., Taylor, C.P., and Vartanian,M.G. (1994) Bioorganic & MedicinalChemistry Letters, 4, 823.

8 (a) Palomo, C., Aizpurua, J.M., Oiarbide,M., Garc�ıa, J.M., Gonzal�ez, A., Odriozola,I., and Linden, A. (2001) TetrahedronLetters, 42, 4829; (b) Palomo, C., Gonzal�ez,A., Garc�ıa, J.M., Landa, C., Oiarbide, M.,Rodr�ıguez, S., and Linden, A. (1998)Angewandte Chemie (International Editionin English), 37, 180; (c) Camps, P., Munóz-

Torrero, D., and S�anchez, L. (2004)Tetrahedron: Asymmetry, 15, 2039; (d) Zelle,R.E. (1991) Synthesis, 1023.

9 Wall, G.M. and Baker, J.K. (1989) Journal ofMedicinal Chemistry, 32, 1340.

10 Ordóñez, M. and Cativiela, C. (2007)Tetrahedron: Asymmetry, 18, 3.

11 Bryans, J.S. and Wustrow, D.J. (1999)Medicinal Research Reviews, 19, 149.

12 (a) Pardridge, W.M. (1985) Annual Reportsin Medicinal Chemistry, 20, 305;(b) Shashoua, V.E., Jacob, J.N., Ridge, R.,Campbell, A., and Baldessarini, R.J. (1984)Journal of Medicinal Chemistry, 27, 659.

13 Lippert, B., Metcalf, B.W., Jung, M.J., andCasara, P. (1977) European Journal ofBiochemistry, 74, 441.

14 (a) Allan, R.D., Bates, M.C., Drew, C.A.,Duke, R.K., Hambley, T.W., Johnston,G.A.R.,Mewett, K.N., andSpence, I. (1990)Tetrahedron, 46, 2511; (b) Olpe, H.-R.,Demieville, H., Baltzer, V., Bencze, W.L.,Koella, W.P., Wolf, P., and Haas, H.L.(1978) European Journal of Pharmacology,52, 133; (c) Ong, J., Kerr, D.I.S., Doolette,D.J., Duke, R.K.,Mewett, K.N., Allen, R.D.,and Johnston, G.A.R. (1993) EuropeanJournal of Pharmacology, 233, 169.

15 Bryans, J.S., Davies, N., Gee, N.S.,Dissanayake, V.U.K., Ratcliffe, G.S.,Horwell, D.C., Kneen, C.O., Morrell, A.I.,Oles, R.J., O�Toole, J.C., Perkins, G.M.,Singh, L., Suman-Chauhan, N., andONeill, J.A. (1998) Journal of MedicinalChemistry, 41, 1838.

16 Burk, M.J., De Koning, P.D., Grote, T.M.,Hoekstra, M.S., Hoge, G., Jennings, R.A.,Kissel,W.S.,Le,T.V.,Lennon,I.C.,Mulhern,T.A., Ramsden, J.A., andWade, R.A. (2003)The Journal of Organic Chemistry, 68, 5731.

17 Thakur, V.V., Nikalje,M.D., and Sudalai, A.(2003) Tetrahedron: Asymmetry, 14, 581.

18 Mazzini, C., Lebreton, J., Alphand, V., andFurstoss, R. (1997) Tetrahedron Letters,38, 1195.

19 Johannesen, S.A., Albu, S., Hazell, R.G.,and Skrydstrup, T. (1962) Journal of theChemical Society, ChemicalCommunications, 2004.


20 (a) Tseng, C.C., Terashima, S., andYamada, S.-I. (1977) Chemical &Pharmaceutical Bulletin, 25, 29;(b) Matthews, J.L., Braun, C.,Guibourdenche, C., Overhand, M., andSeebach, D. (1997) In EnantioselectiveSynthesis of b-Amino Acids (ed. E. Juaristi),Wiley-VCHVerlag GmbH,Weinheim, pp.105–126;(c) Buchschacher, P., Cassal, J.-M., F€urst,A., and Meier, W. (1977)Helvetica ChimicaActa, 60, 2747.

21 Dixon, D.J., Ley, S.V., and Rodr�ıguez, F.(2001) Organic Letters, 3, 3753.

22 Reetz, M.T., Griebenow, N., and Goddard,R. (1995) Journal of the Chemical Society,Chemical Communications, 1605.

23 Adang, A.E.P., Hermkens, P.H.H.,Linders, J.T.M., Ottenheijm, H.C.J., andvan Staveren, C.J. (1994) Recueil desTravaux Chimiques des Pays-Bas, 113, 63.

24 Umezawa, H., Aoyagi, T., Morishima, H.,Matsuzaki,M.,Hamada,H., andTakeuchi,T. (1970) Journal of Antibiotics, 23, 259.

25 (a) Hom, R.K., Fang, L.Y., Mamo, S., tung,J.S., Guinn, A.C., Walker, D.E., Davis,D.L., Gailunas, A.F., Thorsett, E. D.,Leanna, M.R., DeMattei, J.A., Li, W.,Nichols, P.J., Rasmussen, M., andMorton, E. (2000)Organic Letters, 2, 3627;(b) Sun, C.I., Chen, C.H., Kashiwada, Y.,Wu, J.H., Wang, H.K., and Lee, K.H.(2002) Journal of Medicinal Chemistry,45, 4271; (c) Thorsett, E.D., Sinha, S.,Knops, J.E., Jewett, N.E. Anderson, J.P.and Varghese, J. (2003) Journal ofMedicinal Chemistry, 46, 1799;(d) Liang, B., Richard, D.J., Portonovo,P.S., and Joullie, M.M. (2001) Journal ofthe American Chemical Society, 123, 4469.

26 Castejón, P., Moyano, A., Peric�as, M.A.,and Riera, A. (1996) Tetrahedron, 52, 7063.

27 Kambourakis, S. and Rozzell, J.D. (2004)Tetrahedron, 60, 663.

28 (a) Patel, R.N., Banerjee, A., Howell, J.M.,McNamee, C.G., Brozozowski, D.,Mirfakhrae, D., Nanduri, V., Thottathil,J.K., and Szarka, L.J. (1993) Tetrahedron:Asymmetry, 4, 2069; (b) Gou, D.M., Liu,

Y.C., and Chen, C.S. (1993) The Journal ofOrganic Chemistry, 58, 1287.

29 (a) Lu, Y., Miet, C., Kunesch, N., andPoisson, J.E. (1993) Tetrahedron:Asymmetry, 4, 893; (b) Lu, Y., Miet, C.,Kunesch, N., and Poisson, J.E. (1990)Tetrahedron: Asymmetry, 1, 703.

30 (a) Shioiri, T., Sasaki, S., and Hamada, Y.(2003) ARKIVOC, 103; (b) Sasaki, S.,Hamada, Y., and Shioiri, T. (1999) Synlett,453; (c) for the synthesis of diprotected(R)-GABOB from (S)-malic acid, see:Rajashekhar, B. and Kaiser, E.T. (1985)The Journal of Organic Chemistry, 50, 5480.

31 Smrcina, M., Majer, P., Majerov�a, E.,Guerassina, T.A., and Eissenstat, M.A.(1997) Tetrahedron, 53, 12867.

32 Simonelli, F., Clososki, G.C., dos Santos,A.A., de Oliveira, A.R.M., Marques, F. deA., and Zarbin, P.H.G. (2001) TetrahedronLetters, 42, 7375.

33 Martin, C.J., Rawson, D.J., and Williams,J.M.J. (1998) Tetrahedron: Asymmetry,9, 3723.

34 Otaka, A., Yukimasa, A., Watanabe, J.,Sasaki, Y., Oishi, S., Tamamura, H., andFujii, N. (2003) Journal of the ChemicalSociety, Chemical Communications, 1834.

35 Gruner, S.A.W., Locardi, E., Lohof, E.,and Kessler, H. (2002) Chemical Reviews,102, 491.

36 Sanjayan, G.J., Stewart, A., Hachisu, S.,Gonzalez, R., Watterson, M.P., and Fleet,G.W.J. (2003) Tetrahedron Letters, 44, 5847.

37 Gruner, S.A.W., Truffault, V., Voll, G.,Locardi, E., St€ockle, M., and Kessler, H.(2002) Chemistry – A European Journal,8, 4365.

38 Sofia, M.J., Hunter, R., Chan, T.Y.,Vaughan, A., Dulina, R., Wang, H., andGange, D. (1998) The Journal of OrganicChemistry, 63, 2802.

39 Burgess, K., Li, S., and Rebenspies, J.(1997) Tetrahedron Letters, 38, 1681.

40 Royer, F., Felpin, F.-X., andDoris, E. (2001)The Journal of Organic Chemistry, 66, 6487.

41 Okamoto, S., Teng, X., Fujii, S., Takayama,Y., and Sato, F. (2001) Journal of theAmerican Chemical Society, 123, 3462.

References j569

42 Teng, X., Takayama, Y., Okamoto, S., andSato, F. (1999) Journal of the AmericanChemical Society, 121, 11916.

43 El Marini, A., Roumestant, M.L.,Viallefont, P., Razafindramboa, D.,Bonato, M., and Follet, M. (1992) Synthesis,1104.

44 Dexter, C.S. and Jackson, R.W.F. (1998)Journal of the Chemical Society, ChemicalCommunications, 75.

45 Mouri�es, C., Deguin, B., Lamari, F.,Foglietti, M.-J., Tillequin, F., and Koch, M.(2003) Tetrahedron: Asymmetry, 14, 1083.

46 Cordero, F.M., Pisaneschi, F., Batista,K.M., Valenza, S.,Machetti, F., andBrandi,A. (2005) The Journal of Organic Chemistry,70, 856.

47 Poitout, L., Le Merrer, Y., and Depezay,J.-C. (1995) Tetrahedron Letters, 36, 6887.

48 (a) Chakraborty, T.K., Jayaprakash, S.,Diwan, P.V., Nagaraj, R., Jampani, S.R.B.,and Kunwar, A.C. (1998) Journal of theAmerican Chemical Society, 120, 12962;(b) Chakraborty, T.K. and Ghosh, S. (2001)Journal of the Indian Institute of Science,81, 117.

49 (a) Long, D.D., Smith, M.D., Marquess,D.G., Claridge, T.D.W., and Fleet, G.W.J.(1998) Tetrahedron Letters, 39, 9293;(b) Smith, M.D., Long, D.D., Claridge,T.D.W., Fleet, G.W.J., and Marquess, D.G.(1998) Journal of the Chemical Society,Chemical Communications, 2039; (c)Smith, M.D., Claridge, T.D.W., Fleet,G.W.J., Tranter, G.E., and Sansom, M.S.P.(1998) Journal of the Chemical Society,Chemical Communications, 2041.

50 Watterson, M.P., Edwards, A.A., Leach,J.A., Smith, M.D., Ichihara, O., and Fleet,G.W.J. (2003) Tetrahedron Letters, 44, 5853.

51 VanWell, R.M.,Meijer,M.E.A., Overkleeft,H.S., van Boom, J.H., van der Marel, G.A.,and Overhand, M. (2003) Tetrahedron,59, 2423.

52 Peri, F., Cipolla, L., La Ferla, B., andNicotra, F. (2000) Journal of the ChemicalSociety, Chemical Communications, 2303.

53 Graf von Roedern, E., Lohof, E., Hessler,G., Hoffmann, M., and Kessler, H. (1996)

Journal of the American Chemical Society,108, 10156.

54 Suhara, Y., Yamaguchi, Y., Collins, B.,Schnaar, R.L., Yanagishita, M., Hildreth,J.E.K., Shimada, I., and Ichikawa, Y. (2002)Bioorganic and Medicinal Chemistry,10, 1999.

55 Graf von Roedern, E. and Kessler, H.(1994) Angewandte Chemie (InternationalEdition in English), 33, 687.

56 Durrat, F., Xie, J., and Val�ery, J.-M. (2004)Tetrahedron Letters, 45, 1477.

57 Baldauf, C., G€unther, R., and Hofmann,H.-J. (2004) The Journal of OrganicChemistry, 69, 6214.

58 Gardner, R.R., Liang, G.-B., and Gellman,S.H. (1995) Journal of the AmericanChemical Society, 117, 3280.

59 Wipf, P., Henninger, T.C., and Geib, S.J.(1998) The Journal of Organic Chemistry,63, 6088.

60 Belvisi, L., Colombo, L., Manzoni, L.,Potenza, D., and Scolastico, C. (2004)Synlett, 1449.

61 Wang, W., Yang, J., Ying, J., Xiong, C.,Zhang, J., Cai, C., and Hruby, V.J. (2002)The Journal of Organic Chemistry, 67, 6353.

62 Bravin, F.M., Busnelli, G., Colombo, M.,Gatti, F., Manzoni, L., and Scolastico, C.(2004) Synthesis, 353.

63 Manzoni, L., Belvisi, L., Di Carlo, E., Forni,A., Invernizzi, D., and Scolastico, C. (2006)Synthesis, 1133.

64 Hanessian, S., McNaughton-Smith, G.,Lombart, H.-G., and Lubell, W.D. (1997)Tetrahedron, 53, 12789.

65 Estiarte, M.A., Rubiralta, M., Diez, A.,Thormann, M., and Giralt, E. (2000) TheJournal of Organic Chemistry, 65, 6992.

66 (a) Kim, K. and Germanas, J.P. (1997) TheJournal of Organic Chemistry, 62, 2847;(b) Kim, K. and Germanas, J.P. (1997) TheJournal of Organic Chemistry, 62, 2853.

67 Belvisi, L., Gennari, C., Mielgo, A.,Potenza, D., and Scolastico, C. (1999)European Journal of Organic Chemistry, 389.

68 Salimbeni, A., Paleari, F., Canevotti, R.,Criscuoli, M., Lippi, A., Angiolini, M.,Belvisi, L., Scolastico, C., and Colombo, L.


(1997) Bioorganic & Medicinal ChemistryLetters, 7, 2205.

69 Belvisi, L., Bernardi, A., Checchia, A.,Manzoni, L., Potenza, D., Scolastico, C.,Castorina, M., Cupelli, A., Giannini, G.,Carminati, P., and Pisano F C. (2001)Organic Letters, 3, 1001.

70 Alonso, E., López-Ortiz, F., del Pozo, C.,Peralta, E., Mac�ıas, A., and Gonz�alez, J.(2001) The Journal of Organic Chemistry,66, 6333.

71 Khalil, E.M., Ojala, W.H., Pradhan, A.,Nair, V.D., Gleason, W.B., Mishra, R.K.,and Johnson, R.L. (1999) Journal ofMedicinal Chemistry, 42, 628.

72 Genin, M.J. and Johnson, R.L. (1992)Journal of the American Chemical Society,114, 8778.

73 Genin, M.J., Ojala, W.H., Gleason, W.B.,and Johnson, R.L. (1993) The Journal ofOrganic Chemistry, 58, 2334.

74 Ecija, M., Diez, A., Rubiralta, M., andCasamitjana, N. (2003) The Journal ofOrganic Chemistry, 68, 9541.

75 Fink, B.E., Kym, P.R., andKatzenellenbogen, J.A. (1998) Journal of theAmerican Chemical Society, 120, 4334.

76 Trabocchi, A., Menchi, G., Guarna, F.,Machetti, F., Scarpi, D., and Guarna, A.(2006) Synlett, 331.

77 Trabocchi, A., Cini, N., Menchi, G., andGuarna, A. (2003) Tetrahedron Letters,44, 3489.

78 Scarpi, D., Occhiato, E.G., Trabocchi, A.,Leatherbarrow, R.J., Brauer, A.B.E., Nievo,

M., and Guarna, A. (2001) Bioorganic andMedicinal Chemistry, 9, 1625.

79 Trabocchi, A., Occhiato, E.G., Potenza, D.,and Guarna, A. (2002) The Journal ofOrganic Chemistry, 67, 7483.

80 Nielsen, P.E., Egholm,M., Berg, R.H., andBuchardt, O. (1991) Science, 254, 1497.

81 (a) Hyrup, B. and Nielsen, P.E. (1996)Bioorganic and Medicinal Chemistry, 4, 5;(b) Uhlmann, E., Peyman, A., Breipohl,G., and Will, D.W. (1998) AngewandteChemie (International Edition in English),37, 2796.

82 P€uschl, A., Tedeschi, T., and Nielsen, P.E.(2000) Organic Letters, 2, 4161.

83 (a) Karig, G., Fuchs, A., B€using, A.,Brandstetter, T., Scherer, S., Bats, J.W.,Eschenmoser, A., and Quinkert, G. (2000)Helvetica Chimica Acta, 83, 1049;(b) Schwalbe, H., Wermuth, J., Richter, C.,Szalma, S., Eschenmoser, A., andQuinkert, G. (2000) Helvetica ChimicaActa, 83, 1079.

84 Casimir, J.R., Didierjean, C., Aubry, A.,Rodriguez, M., Briand, J.-P., andGuichard, G. (2000) Organic Letters,2, 895.

85 Grotenbreg, G.M., Christina, A.E.,Buizert, A.E.M., van der Marel, G.A.,Overkleeft, H.S., and Overhand, M. (2004)The Journal of Organic Chemistry, 69, 8331.

86 Brittain, D.E.A., Watterson, M.P.,Claridge, T.D.W., Smith, M.D., and Fleet,G.W.J. (2000) Journal of the ChemicalSociety, Perkin Transactions 1, 3655.

References j571

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