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Current Organic Synthesis, 2008, 5, 173-185

173

Chemistry of Norbornane/ene and Heteronorbornane/ene -Amino Acids Ferenc Csende, Ferenc Fülöp* and Géza Stájer Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary Abstract: The structures, biological properties, preparations and synthetic applications of norbornane/ene bicyclic and heteroatombridged -amino acids are discussed. These compounds are rare and unique -alanine derivatives which can be used as bifunctional synthons for the preparation of heterocycles. Through peptidation, they form oligopeptide-like molecules with special helical structures.

Key Words: (Hetero)bicyclic -amino acids, biological activity, heterocycles, retro diels-alder reactions, ugi reactions, peptide syntheses. 1. INTRODUCTION In recent years, there has been increasing interest in alicyclic amino acids with particular regard to their syntheses and pharmacological applications. Reviews have appeared on the synthesis of -amino acid containing hybrid peptides [1] and preparations chemical, physical and biological properties of -alanine and its unnatural or condensed-skeleton derivatives [2-7]. We focus here on the bicyclic -amino acid derivatives norbornane/ene, and heteronorbornane/ene (oxa-, aza- and thianorbornane/ene) (Scheme 1).

NH2

COOH COOH X

NH2 diendo

NH2 1 X = CH2, O, NH, S COOH NH2 NH2 endo-NH2, exo-COOH

6

COOH exo-NH2, endo-COOH

Scheme 1.

The heteroatoms O, S, N and P may occur at position 7 in the heteronorbornane/ene (7-heterobicyclo[2.2.1]heptane/ene) -amino acids, which are suitable for syntheses in heterocyclic or peptide chemistry. In the Diels-Alder reactions of thiophene and thiophene oxide with different dienophiles, Margetic et al. [8] found experimentally that the -bond of S-bridged norbornenes is unreactive in comparison with those in the oxa- and azanorbornene analogs. Ab initio calculations were used for the location of transition states and the estimation of activation energies for the Diels-Alder reactions with the cyclic dienes cyclopentadiene, furan and pyrrole. The molecular and electronic structures of norbornene 2 and 7heteronorbornene models 3-10 were examined in detail (Scheme 2). A comparison of the calculated double bond pyramidation angles demonstrated that the extent of pyramidation was not consistent with the experimental reactivity data. The pyramidation angle is not larger in 6 than in 3. *Address correspondence to this author at the Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary; E-mail: [email protected]

1570-1794/08 $55.00+.00

N

3 1

2

2

3 O

S

N

O

4 5

6

COOH

diexo

7

S

7

4 O S

8

5 P

P

9

10

Scheme 2.

The skeletons 2-6 have been well studied in practical chemistry. In this paper, we survey the -amino acid analogs of bicyclo[2.2.1]heptane/ene, and 7-oxa-, 7-aza- and 7-thiabicyclo[2.2.1]heptane/ ene. These are often used as synthons for the preparation of saturated or partially saturated heterocyclic rings, directly or via retro Diels-Alder (rDA) reactions, and they are of stereochemical interest [9-12]. In some cases, these amino acids are key compounds for the preparation of unique heterocycles. The bicyclic -amino acids can also serve as valuable conformationally constrained units and they have been built into pseudopeptides (oligomers or foldamers) or peptides, in which two peptide chains run in parallel, but are offset due to the presence of a urea linkage [13-15]. The -peptides, i.e. oligomers of -amino acids, contain only a few residues (units) which may form stable helices; moreover, they are stable to common peptidases for days [16]. These peptides have revealed that the diendo-norborn-5-ene unit induces the formation of a parallel sheet conformation between two peptide chains. Another analogous peptide residue encouraged the formation of an antiparallel -sheet by acting as a -turn mimic [17,18]. The -turns and -sheets are important secondary structure elements of proteins, which are known to be responsible for certain biological properties [19]. 2. BIOLOGICAL PROPERTIES The bicyclic and heterobicyclic -amino acids and alicyclic analogs, have marked pharmacological effects. They are effective analgesics, the 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (ABHCA) has anti-allodynic effects or they are potent 2 ligands (Ki = 150 nM) [20]. ABHCA acts as potential 2 ligand, depending on their plasma and brain concentrations and ratios at different times, and the effects of their oral administration to rats were comparable to those of other compounds. Moreover, a very late antigen-4 (VLA-4) effect was implicated in inflammatory and autoimmune disease states. Chang et al. studied a series of -amino acids as VLA-4 antagonists, and found that compound 11 (Scheme 3), administered orally, was a potent agent (IC50 = 54 nM) with good (49%) bioavailability in rats [21]. Others prepared alicyclic -

© 2008 Bentham Science Publishers Ltd.

174 Current Organic Synthesis, 2008, Vol. 5, No. 2

Csende et al.

COOH

CONH2 N

O HN

ArO2S

SO2Ar N

11

12 Ar = 4-ClPh R = CF3, CN

Ar = 3,5-diClPh

R

O COOH

NHOH X

SO2 NH NHSO2Ph

13 diendo, diexo X = CH2, O, NH

O

14 N

Scheme 3.

amino carboxamides such as 12, which inhibits -amyloid peptide (-AP) production, and hence are potentially useful in the treatment of Alzheimer’s disease and other conditions characterized by the aberrant extracellular deposition and accumulation of -AP, e.g. in Down’s syndrome [22]. A novel study described the synthesis and biological effects of cycloalkane-, norbornane- and 7-heteronorbornane-fused -sulfonamide hydroxamic acids (13) as inhibitors of metalloproteinase, which were effective in the treatment of diseases or disorders mediated by TNF-, such as arthritis, tumor metastasis, tissue ulceration, multiple sclerosis or pulmonary fibrosis [23]. Asymmetric synthesis of the potent thromboxane A2 (TXA2) receptor antagonist, the compound S-1452 (14), was achieved from 3endo-bicyclo[2.2.1]heptene-2-exo-carboxylic acid via the key-step epimerization and methanolysis, affording a half-ester. Initially, the racemic compound was developed, but studies of the binding affinity of different isomers to the TXA2/PGH2 receptor showed that the R isomer was 20 times more potent than the S isomer [24]. Three stereoisomers of racemic 14 were synthetized and the IC50 values of the sodium salts were established for platelet aggregation, using rat platelets and human platelet-rich plasma [25]. Several novel analogs of 14 were prepared, which are dual antagonists to the TXA 2 and PGD2 receptors, and pharmaceutically useful for the treatment of systemic mastocytosis, systemic mast cell activation disorders, tracheal contraction, asthma, allergic rhinitis, conjuctivitis and urticaria [26]. The oxabicyclo analogs of 14 have been found to be similarly potent thromboxane (TXA2-receptor) antagonists which strongly inhibit platelet aggregation or vasoconstriction [27]. Some 7-azabicyclo[2.2.1]heptane/ene derivatives exhibited analgesic and anti-inflammatory activity [28], while heteroarylsubstituted agents were effective for the treatment of CNS diseases, e.g. as anti-psychotic agents, or active in Alzheimer’s disease, senile dementia, schizophrenia, psychosis and depression or anxiety [29]. The compounds have the exo orientation at C-2 and the S

configuration at C-1 (Scheme 4), or the R configuration at C-2 and C-4 of the 7-azabicyclo[2.2.1]heptane ring. Unexpectedly, the derivatives have much higher activities relative to the compounds without 1S,2R,4R stereochemistry within the 7-azanorbornane ring. For example, the activity ratio for compounds with the 1S,2R,4R configuration may be 100 times higher than for other stereochemical configurations [29]. The 7-azabicyclo[2.2.1]heptane/ene analogs were observed to be very effective cholinergic receptor ligands [30]. R3 N 1 4

2

R1 = H, alkyl, aryl

R2 X Ar

N

15

R2 = H, alkyl, aryl, Ac, carboxyl

R1

R3 = H, alkyl X = O, S

Scheme 4.

3. SYNTHESIS OF BICYCLIC -AMINO ACIDS 3.1. Synthesis from -lactams The stereoselective (diexo-selective) 1,2–dipolar cycloaddition of chlorosulfonyl isocyanate (CSI) to the cycloalkenes, (bi)cycloalkene and diene (17 and 16) results in N-chlorosulfonyl--lactams, which react with sodium sulfite or thiophenol/pyridine, for example, to give bicycloalkane-fused -lactams 18 and 19 [31,32]; these undergo acidic hydrolysis to yield ali(bi)cyclic -amino acids (20 and 21) [33,34]. From norbornene or norbornadiene (17 and 16), 3exo-aminobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid (20) and 3-exo-aminobicyclo[2.2.1]heptane-2-exo-2-carboxylic acid (21) were obtained in medium yields [35]. The acidic opening of lactams results in the hydrochlorides in an exothermic reaction. Ionexchange chromatography on a resin column led to the free amino acids 20 and 21 (Scheme 5). O

1. CSI, Et2O, 0 °C 2. Na2SO3, KOH

1. aq. HCl, RT 2. ion-exch. resin NH

16: norbornadiene 17: norbornene Scheme 5.

18: norbornene -lactam 19: norbornane -lactam

COOH NH2 20: norbornene -amino acid 21: norbornane -amino acid

Chemistry of Norbornane/ene and Heteronorbornane/ene -Amino Acids

The lipase-catalyzed highly enantioselective ring opening of the racemic azetidinones 18 and 19 (E > 200) in diisopropyl ether at 70 °C [36] furnished exo-3-azatricyclo[4.2.1.02,5]nonen-4-one or its dihydro enantiomers (Scheme 6).

Current Organic Synthesis, 2008, Vol. 5, No. 2

give anhydride 30, Hofmann degradation furnished exo-6-phenylsubstituted diendo bicyclic ß-amino acid 31 [40].

O +

1. benzene/AlCl3 2. Ac2O

COOH

COOH NH2

29

HN

Ph

O O

COOH

30

20a: 1S,2R,3S,4R (unsaturated) 21a: 1R,2R,3S,4S (saturated)

Ph

18% HCl, reflux 3 h

lipolase, (i-Pr)2O

175

COOH

70 °C, 8-11 days

31

O

1. NH4OH 2. Br2/NaOH 3. Dowex 50

NH2

Scheme 8.

O

HOOC H2N HCl

NH (±) diexo 18 and 19

20b: 1S,2R,3S,4R (unsaturated) 21b: 1R,2R,3S,4S (saturated)

All-endo-3-Amino-6-hydroxynorbornene-2-carboxylic acid 35 and some derivatives were prepared by iodolactonization, which was performed with iodine or N-iodosuccinimide in two phases (Scheme 9). Iodolactone 33 was reduced to 34 with Bu3SnH, and lactone 34 was then opened by acidic hydrolysis, which yielded exclusively 6-endo-hydroxylamino acid 35 [41].

Scheme 6.

3.2. Synthesis from 1,2-Dicarboxylic Acid Derivatives A number of diastereomerically pure 1,2-dicarboxylic acid anhydrides are commercially available or can be easily prepared in 98% yield by the Diels-Alder reaction of cyclopentadiene 22 or furan 23 and maleic anhydride 24 under mild conditions (Scheme 7). This reaction is also stereocontrolled, but whereas diendoanhydride 25 was formed from cyclopentadiene, the furan–maleic anhydride reaction gave the diexo adduct 26 (X = O). diendo 25 can be isomerized to diexo 26 (X = CH2) almost quantitatively at 190 °C [37]. 26 (X = CH2) can also be prepared in an exo-selective Diels-Alder reaction by photolysis at 300 nm in dry EtOH, in the presence of Et3N [38]. With furan 23 as diene, amidation of anhydride 26 (X = O), followed by a modified Hofmann degradation with hypochlorite, results in 3-exo-amino-7-oxabicyclo[2.2.1]hept5-ene-2-exo-carboxylic acid (27) [39], while from cyclopentadiene 22 the 3-endo-aminobicyclo[2.2.1]hept-5-ene-2-endo-carboxylic acid (28) is obtained. O

O X +

Et2O

O

O

X

NHBoc 32

25: diendo (X = CH2) 26: diexo (X = CH2, O)

24

O 33 O Bu3SnH CH2Cl2

HCl/H2O NHBoc

NH2 . HCl HO

O

COOH 35

34

O

Scheme 9.

Diexo-7-Thiabicyclo[2.2.1]hepteneamino acid (38) and its derivatives were prepared from the bicylic anhydride 37. As the thiophene exhibited little tendency to react as a 4 component by DielsAlder reaction, vigorous conditions (high pressure) were applied for the cycloaddition [42,43]. S

O S

O

15 kbar, 100 °C +

O

O CH2Cl2

1. NH4OH 2. NaOCl

3. ion-exchange, Dowex 50

36

O

O

37

O 24 S

COOH

COOH

NH2 27

NHBoc CH2Cl2

COOH

O

O

22: X = CH2 23: X = O

I I2, KI, NaHCO3

COOH 28

NH2

NH2

Scheme 7.

High exo selectivity was observed in the Friedel-Crafts reaction of benzene on the C=C bond of norbornenedicarboxylic acid 29 with AlCl3 as catalyst (Scheme 8). After dehydration with Ac2O to

38 Scheme 10.

A mixture of diexo and diendo-7-azanorbornene anhydride 41 was prepared by osmium-induced cycloaddition from pyrrole 39 and maleic anhydride 24 (in a 4:1 ratio, Scheme 11) [44]. In another


Csende et al.

case, cycloaddition in MeCN with dimethyl fumarate led to the endo-exo-dimethoxycarboyl-7-azanorbornane as intermediate, in an overall of yield about 42% [26]. O NH

+

O

O

Os(NH3)5 39

RT, 5 min

(H3N)5Os

MeCN

NH

O

O

40

24

O

diexo:diendo = 2:1 H2, Pd/C

1 atm, MeCN

O

NH COOH

Hofmann degradation

NH

O

NH2 42

O

41

Scheme 11.

The unnatural norbornene- and oxanorbornene-fused N-protected -amino esters can be obtained by means of Curtius degradation. The dicarboxylic monoesters (43 and 44) prepared from bicyclic anhydrides 25 and 26 by methanolysis were activated by treatment with ethyl chloroformate and Et3N (Scheme 12). Following the addition of an aqueous solution of NaN3, the thermal rearrangement resulted in isocyanates; these reacted with tert-BuOH in the presence of p-toluenesulfonic acid (PTSA) to give protected amino esters, which were converted to -amino acids 45 and 46 in a 1. ClCOOEt Et3N/THF 2. NaN3

COOMe X

quantitative yield by careful saponification with NaOH [45,46]. The intermediate isocyanates were also treated with PTSA–water to afford primary amines as key intermediates in the synthesis of potent norbornyl thromboxane TXA2 receptor antagonists [47,48]. The enantioselective methanolysis or opening with benzyl alcohol of bicyclic meso-anhydrides mediated by cinchona alkaloids led to dicarboxylic acid monomethyl esters with 96-99% ee. Some unnatural N-protected -amino esters were transformed by Curtius degradation of the corresponding acyl azides obtained from the half-esters. After cleavage of the protecting groups with NaOH solution, catalytic hydrogenation gave free amino acids in good yields [49,50]. Desymmetrization of diendo-norborn-5-ene-2,3-dicarboxylic anhydride by proline esters has been used to prepare conformationally constrained pseudopeptides with two parallel peptide chains. After Curtius rearrangement of the desymmetrization adduct made from the corresponding isocyanate, the product was used for the preparation of peptides incorporating the endo-2-aminonorborn-5enecarboxylic acid unit [15]. A modified Curtius degradation with Me3SiCN was applied for an unusual ethylene-bridged analog, and the enantiomerically pure trans-(9,10)-dihydro-11-aminoethanoanthracene-12-carboxylic acid was prepared from the Diels-Alder adduct of anthracene and maleic anhydride [51]. The base-induced Lossen rearrangement involves the decomposition of hydroxamic acids or their O-acylated or sulfonylated derivatives, e.g. N-benzenesulfonyloxy-diendo-1,2-norbornane/ene dicarboximides 47 and 48 (Scheme 13). After acidic treatment, reaction via the isocyanate intermediate in strong base, at 100 °C resulted in the corresponding -amino acids 28 and 49 [52,53]. The norbornene N-benzenesulfonyloxy derivative was found to rearrange smoothly in MeOH containing Et3N. N-Hydroxyimides of 47 and 48 were prepared from the anhydrides with aqueous NH2OH.

COOMe X

X CON3

COOH 43: diexo 44: diendo

COOMe

N

C

1. t-BuOH, PTSA 2. NaOH, MeOH

MeOH O

COOH O

X

25: diexo 26: diendo

X NH2

O X = CH2, O


Scheme 12.

COOH

COOH O

NHOSO2Ph NaOH 100 °C

N C O O H H

COOH O H HN 1. HCl 2. IRA-400

O NOSO2Ph O 47: norbornane 48: norbornene Scheme 13.

COOH NH2 28: norbornene 49: norbornane

O

O



Methyl 3-bromopropiolate reacted smoothly with pyrrole derivatives to afford the [4+2] adducts in good yields. Heating of the bromoester with 5 equiv. of N-protected pyrrole 58 at 90-95 °C for 30 h gave bicyclic bromo ester 59 (Scheme 16). On treatment with Et2NH and Et3N in MeCN, followed by acidic hydrolysis, 59 afforded -oxo ester 60 as a mixture of isomers (endo:exo ~7:1) [60]. After reduction, R--methylbenzylamine addition in the presence of ytterbium(III) triflate, reaction with sodium triacetoxyborohydride, hydrogenation and deprotection of the tert-butoxycarbonyl group with TFA resulted in the exo-endo--amino acid 61 [23].

3.3. Formation of Bicyclic Amino Acids by Diels-Alder Reactions The Diels-Alder adducts 50 and 51 of alkyl (E)-3-nitroacrylates and furan 23 or cyclopentadiene 22 led, after reduction, to a mixture of racemic endo–exo isomer amino acids 52 and 53, in 90% yield (Scheme 14). In CHCl3 at low temperature (-20 ºC), endo-nitro adducts 50 and 51 were isolated in 72% yield [21,54-56]. Cyclopentadiene 22 with methyl- and phenyl-substituted ethyl 3nitrocrotonates also selectively gave endo-nitro derivatives, which were reduced by catalytic hydrogenation with Raney-nickel in EtOH at room temperature to amino esters, in almost quantitative yield [57]. Under neat conditions, the highly diastereoselective Diels-Alder reaction between cyclopentadiene 22 and ethyl (Z)-2N-Boc-amino-3-nitroacrylate afforded 2-amino-3-nitronorbornene2-carboxylic acid derivatives, which, after catalytic hydrogenation, resulted in the norbornaneamino acid [58]. The nitro derivatives 50 and 51 serve as useful synthons for the preparation of bicyclic glutamic acid analogs. Recently, 1,2- and 1,4-cycloadditions of ethyl -nitrocinnamate to cyclopentadiene were achieved, and the configurations of the adducts were studied [59]. By means of the Diels-Alder reaction, the multi-step diastereoselective synthesis of 2-aminobicyclo[2.2.1]heptane-2,3-dicarboxylic acids as conformationally constrained (S)-aspartic acid analogs was achieved (Scheme 15) [60]. The intermediate adducts 55a and 55b were readily prepared from the reaction of cyclopentadiene and a chiral oxazolone 54 derived from (R)-glyceraldehyde, in n-hexane at room temperature. The reaction afforded the major endo-amino adduct (57a, d.r. 96:4) or the major exo adduct (57b, d.r.>98:2) in a ratio of 70:30 [60].

COOR

O2N

X

4. REACTIONS OF THE BICYCLIC AMINO ACIDS 4.1. Synthesis of Heterocycles From amino acids, bicyclic difunctional derivatives have been prepared by esterification, followed by ammonolysis, hydrazinolysis or reduction with LAH to obtain key compounds for the preparation of heterocycles (Scheme 17). On refluxing in EtOH, stereoisomeric norbornane/ene -amino acids or esters reacted with benzimidates in the presence of an acid catalyst to afford methano-4(3H)-quinazolinones 67; the tetrahydro derivatives underwent a mild thermal rDA reaction at their melting points and gave 2-aryl-4(3H)-pyrimidinones (68) (Scheme 18) [10, 62]. 3-endo-Aminobicyclo[2.2.1]hept-5-ene-2-endo-carboxylic acid (28) was acylated with aroyl chlorides, then treated with SOCl2 and cyclized in the presence of Et3N to yield 2-aryl-5,8-methano4a,5,8,8a-tetrahydro-3,1-benzoxazin-4-ones (70) (Scheme 19) [63]. The product was heated at 150 ºC for 10 min, then purified on a

X COOR

CHCl3, –20°C

1. Zn, HCl, EtOH or H2, PtO2, EtOAc 2. HCOONH4 10% Pd/C, MeOH

X COOR

NH2

NO2

22: X = CH2 23: X = O

52: exo–endo, X = CH2 53: exo–endo, X = O

50 and 51 R = Me, Et

Scheme 14.

O

O O

O

O

O Ph

22 N

N O

Ph

+

n-hexane, RT, column chromatography

54

N O 55a

O

O

O

Ph

O

55b

NaOMe, MeOH

COOMe NHCOPh

56

Scheme 15.

O

1. H2, Pd/C 2. HCl, MeOH

COOH

COOH

NH2

3. NaIO4, RuCl3 4. 6 M HCl O

177

COOH 57a

NH2 57b

COOH


Csende et al.

Boc

Br COOMe

Br

N

NBoc

90-95 °C, 30 h

COOMe 59

58

1. Et2NH, Et3N (in MeCN) 2. 10% HCl, RT, 4 h 3. H2, 10% Pd/C

1. Yb(III) triflate, reflux, 3 h H2N NH2

Ph O

Me

NH

NBoc 2. Na(OAc)3BH 3. 20% Pd(OH)2/C, MeOH, H2, 19 h 4. TFA, CH2Cl2

COOMe 61

COOMe 60

Scheme 16.

COOH

SOCl2, EtOH

NH3/MeOH 7 days, RT

COOEt

NH2

CONH2

NH2

NH2


65: diexo, diendo

62: diexo, diendo N2H4/EtOH

LAH/Et2O

reflux CONHNH2

LAH/Et2O

OH

NH2

NH2

NH2

64: diexo, diendo

NH2

63: diexo, diendo

66: diexo, diendo

Scheme 17.

NH Ar COOH

NH2

O

O

OEt EtOH, H+

180-250 °C 10 min

NH

reflux, 10 h

N


Ar

NH N

–

67a: diexo, diendo

Ar

68

Ar = Ph, 3-ClPh, 4-ClPh, 4-MePh Scheme 18.

COOH

O

COOH O HN

2. HCl

NH2 28

O

1. SOCl2 2. Et3N

1. ArCOCl, aq NaOH

69

O N

O N

Ar

71

70 Ar

150 °C, 10 min

Ar Ar = Ph, 4-MePh, 4-ClPh, 3,4-diClPh

Scheme 19.

silica gel column, resulting in 6H-1,3-oxazin-6-ones 71 via a rDA reaction. From 45 and 46, with SOCl2, the N-Boc-protected amino acid chlorides were made, followed norbornene- and 7-oxanorbornene-

condensed 1,3-oxazine-2,6-diones (72 and 73) were prepared (Scheme 20) by intramolecular cyclization and simultaneous cleavage of the protecting group. Followed pyrolysis yielded 1,3oxazine-2,6-dione 74 by cycloreversion [46].



O

O COOH

1. [(CH3)3COCO]2O 2. SOCl2, THF

X

179

RT, 2 h

NH2

160 °C, 10 min

O

O

X NH

O

NH 72 and 73 X = CH2, O

45: diexo (X = CH2, O) 46: diendo (X = CH2)

O

74

Scheme 20.

4(1H)-ones (82 and 83); the norbornene-fused derivatives readily decompose to 2,3-dihydrothioxopyrimidin-4(1H)-ones 84 when heated above their melting points, splitting off cyclopentadiene [66]. The condensation of diexo and diendo-amino acid esters 85 with 2-chloroethyl- or 3-chloropropyl isothiocyanates afforded fused thiazolo[2,3-b]pyrimidin-5-ones (n = 1) and pyrimido[2,1b]thiazin-6-ones (86). After heating of the norbornene derivatives at about 140 ºC, new bicyclic heterocylic ring systems 87 were formed in good yields (70-83%) (Scheme 23) [67]. The cyclization of N-substituted--aminocarboxamides 65 prepared by mixed-ester formation with orthoformic esters resulted in methanoquinazolinones 88. The norbornene derivatives, without isolation and by heating at higher temperature, gave 2,3-disubstituted pyrimidin-4(3H)-ones 89 by rDA reaction [68]. On cyclization with carbonyldiimidazole (CDI) to 90 and heating, the corresponding diones 91 were obtained (Scheme 24).

The reactions of 2-carboxybenzaldehyde 75 with amino acids 21 and 28 led to isoindolo[2,1-a][3,1]benzoxazinediones 76. When heated, the norbornene derivatives 76 (and also 80) underwent retrodiene decomposition by the splitting-off of cyclopentadiene to give 1,3-oxazino[2,3-a]isoindolonedione 77 (or pyrrolo[1,3]oxazinedione 81) (Scheme 21) [64,65]. Whereas the cyclization of diendo-3-aminobicyclo[2.2.1]heptane/ene-2-carboxylic acids 28 with 4-oxopentenoic acid (levulinic acid) 78 yielded the expected methanodioxopyrrolo[1,2-a][3,1]benzoxazonediones 80, diexo norborneneamino acid gave 79a as sole product, while norbornaneamino acid 21 afforded the saturated derivative of 79a together with 79b [65]. By the reactions of norbornane/ene amino acids 21 and 28 with alkyl- and aryl isothiocyanates, the corresponding thioureas 84 were formed (Scheme 22). Cyclization by acid catalysis furnished 3-substituted 2-thioxohexahydro- and tetrahydro-5,8-methanoquinazolinCHO O COOH

COOH

O

75 chlorobenzene reflux

NH2 21: diexo 28: diendo

O (norbornene)

N

N

–

O

O

O

76: diexo, diendo

77

COOH

Me

O

78

O

O

O O O

N O

N

Me

(norbornene)

O

–

O N

O

Me

N

Me

O

O 79a

79b

80

81

Scheme 21.

O COOH

NH2 21: diexo 28: diendo

1. RNCS, EtOH reflux, 2 h 2. reflux, EtOH/HCl

(norbornenes) 180-220 °C 10 min

NR NH

S

82: diexo 83: diendo R = Me, Et, Ph, 4-MePh, 4-ClPh

Scheme 22.

– C

O NR NH 84

S


Csende et al.

O

NCS ( )n Cl Et3N, EtOH

COOEt

NH2 85: diexo, diendo

N

RT, 24 h

N

n = 1, 2

86

O

(norbornenes) 140 °C 20 min

( )n S

N

–

( )n S

N 87

Scheme 23.

R2C(OEt)3 reflux

NHR1

NR1 N

NH2 65

4. HBr/AcOH 5. Na2CO3

NR1

–

R2

R2

N

88

CDI, benzene reflux, 8 h

1. BzOC(O)Cl 2. i-BuOC(O)Cl 3. R1NH2

O

O

O

89

O

O

NR1

NR1

COOH NH NH2

O

–

NH

90


O

91

R1 = Me, Ph, Bz; R2 = H, Me, Et

Scheme 24.

O COOEt O

COOEt KOCN NH2 . HCl

MeOH

85: diexo, diendo

NH

O

(norbornenes),

NH

NH2

NH

–

xylene NH

92

O

NH

93

O

94

Scheme 25.

The HCl salts of ethyl 2-amino-norbornane/ene-3-carboxylates 85, with cyanate in MeOH gave urea esters 92, which were cyclized to the fused 5,6-dihydrouracils 93 (Scheme 25). On heating, the norbornene derivatives yielded 2,4-pyrimidinedione 94 through the splitting-off of cyclopentadiene [69].

Starting from the HCl salts with thiophosgene, esters of 85 gave isothiocyanates 95, which underwent ammonolysis and cyclization to furnish first 96 and then, on heating of norbornene derivatives, 97 (Scheme 26) [70]. The reaction of tricyclic 96, with dimethyl acetylenedicarboxylate (DMAD) led to the tetracyclic compounds 98. O COOEt

COOEt

NH2

NCS

85: diexo, diendo

NH

95 DMAD O

N

96 (norbornenes) O

N

NH

S

O

COOMe 98

Scheme 26.

NH

NH3/MeOH

CSCl2 NaHCO3

NH 97

S

–

S


The preparation and stereochemical studies of norbornane/enefused dihydro-1,3-oxazines, 1,3-oxazin-2-ones and 1,3-oxazine-2thiones 99-101 were achieved by subjecting diexo and diendo amino acids 21 and 28 to reduction with LAH to aminoalcohols. These were cyclized to heterocycles with ethyl chloroformate, arylimino ethers and MeONa or CS2 (Scheme 27) [71,72].

O NH

O

O O

N

99: diexo, diendo

NH

Ar

S

101: diexo, diendo

100: diexo, diendo Ar = Ph, 4-ClPh, 3-ClPh, 4-MePh

Scheme 27.

From bicyclic aminoalcohols, polycyclic methylene-bridged 3,1-benzoxazinones 102-104 were obtained by refluxing with -oxo acids or esters in dry toluene, in the presence of PTSA as catalyst (Scheme 28) [73-76].


181

4.2. Ugi-Reactions with -amino Acids The four-component Ugi-reaction (U-4CR) is a valuable tool in organic chemistry for the generation of amino acid derivatives in a straightforward manner: by condensing an aldehyde, amine, carboxylic acid and isocyanide in a one-pot reaction [79]. An intramolecular version of the Ugi-reaction has also been reported, where two functional groups are present in the same molecule. The -amino acids as bifunctional compounds and the Ugi-4-center-3components (U-4C-3C) are well known. Fülöp et al. recently reported the parallel liquid-phase synthesis of cycloalkane-fused Nsubstituted ß-lactams from ß-amino acids in U-4C-3C reactions (Scheme 30) [80]. For example, 3-exo-aminobicyclo[2.2.1]heptane2-exo- (20) and 3-exo-aminobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid (21) were reacted with cyclohexyl isocyanide and 4nitrobenzaldehyde in MeOH at room temperature to yield azetidinones 110 and 111 in good yields (64-86%) via the unstable oxazepinone ring system 109. The solution-phase library prepared was purified by column chromatography. O COO

R2

O N

O

O

O

NH

Ar

Ar N

N

N

O

O

R1

109

R1 R1CHO

O

103: diexo, diendo

102: diexo, diendo

NH

R2NC

104: diexo, diendo

O O

COOH

Ar = 4-MePh

N

Scheme 28.

From aminonorbornane/eneamino acid hydrazides (64) with 2aroylbenzoic acid, fused-skeleton heteropentacycles 105 were prepared (Scheme 29) [77]. The reactions of hydrazides with cyclohexane oxoacids furnished methanohexahydroquinazolino[2,3-a]phthalazines (106). For retrodiene preparation, compound 107 was isolated unexpectedly; on heating, this underwent cycloreversion to yield aminopyrimido[2,1-a]isoindoledione. Boiling of diexoor diendo-2-aminobicyclo[2.2.1]hept-5-ene-3-carbohydrazides (64) with 3-aroylnorbornenecarboxylic acid in toluene yielded pyrimido[1,2-b]pyridazine 108 directly in a double rDA process [78]. O N

Ar

NH2

O 1. NaOH aq, dioxane 2. Pd/C, H2, MeOH

COO

112

113

R1 O N

N

N

NH3

COOMe

O N

O

Similarly, the intramolecular Ugi-reaction of oxanorbornene derivative 112 resulted in tricyclic ß-lactams 114 through a zwitterionic form; according to the NMR analysis, the mixture contained diastereomers in a ratio of 50:50 – 71:29 (Scheme 31) [81].

106: diexo, diendo

O

N

Scheme 30.

Ar

N

105: diexo, diendo

Ar

NH

R1CHO, R2NC MeOH R2

O O

Ar

114

N

H H

R1 = i-Pr, Ph, Bn; R2 = n-Bu, t-Bu

108 Scheme 31.

107 Ar = 4-MePh Scheme 29.

N

R2

110: diexo-norbornane 111: diexo-norbornene

20: diexo-norbornane 21: diexo-norbornene

NHCbz

N

N

R1

O

O N

NH2

NH

A comparative study of the multicomponent Ugi-reaction was carried out both in MeOH and in water, the products being ßlactams 115 and 116 in different diastereomeric ratios. It was found


Csende et al.

CHO

CHO

COOH NH2

COOH NC

NH2 NH2

CHO

NC

COOH

CHO

COOH NH2

A

B

C

OMe

O O

O N

R2

115

N

116

NH R1

O R1 HN

R1 = t-Bu, Et, Ph, 4-MeOPh R2 = t-Bu, cyclohexyl

R2

R1 = Ph; R2 = t-Bu

Scheme 32.

that the concentrations and solubilities of the starting materials influenced the reaction, and substituents R1 and R2 also partly determined the ratio of the diastereomers in the lactams obtained (Scheme 32) [82]. With t-Bu subtituents (R1 = R2 = t-Bu), the diastereomeric ratio was 87:13 in MeOH and 100:1 in water. On application of U-4C-3C, when the building blocks of the Ugi-libraries were generated from the bicyclic ß-amino acids A, isocyanides B and aldehydes C, water was an inexpensive and environmentally friendly solvent [83]. Moreover, the work-up and purification of the products were simpler than in any other way. 4.3. Application in Peptide Synthesis Because of their regioselectivity toward nucleophiles, the bridged azatricyclic anhydrides are interesting intermediates. Thus, diexo-fused 1,3-oxazinediones 72 and 73 were coupled with di-tertbutoxycarbonate (Boc2O) in THF and Et3N, followed by the addition of glycine methyl ester, which afforded dipeptides 117 and 118 in good yields (Scheme 33) [46]. Doerksen et al. synthetized novel conformationally constrained 7-oxanorbornene ß-peptides [84] and characterized them by density functional theory-computed 1H NMR chemical shifts and geometries of the dimer and trimer, each adopting a consecutive 8membered hydrogen-bonded ring conformation (Scheme 34). The preference for a single conformation containing 8-helices appears to be a result of the constraints imposed by the oxanorbornene ring. For the preparation of dimeric or trimeric oxanorbornene ß-amino acid derivatives 119, epimerization in the first step was followed by conversion to the N-Boc acid chloride and to the TFA salt. The X

O

X 1. Boc2O, THF RT, 4 h

O NH 72: X = CH2 73: X = O Scheme 33.

coupling of 120 with amino ester 121 provided dimer 122, after conversion of the methyl ester to methylamide and replacement of the tert-butylcarbamate to methylcarbamate. Trimer 123 was prepared by the same sequence of reactions with a Boc or methoxycarbonyl C-terminus. Through conventional peptidation, bicyclic diexo-ß-amino acids have been applied for the design, synthesis and characterization of oligomers 125 [85]. Oligomerization of the amino acid enantiomers was achieved as described above (Scheme 35) [86]. The oligopeptides were purified by column chromatography on silica gel. The tuning of the conformational space of the ß residues was represented by the dihedral angles , and (convention of Balaram) [87], which provide a variety of folding possibilites. Homo and hetero oligomers based on bicyclic diexo-norbornene ßamino acid residues with gauche conformation around form short and stable right-handed helices (Scheme 36). The Newman projections about the C-C axis for the two enantiomers of the norborneneamino acid unit according to Chandrasekhar et al. are as follows (Scheme 37) [85]. For incorporation of the endo-norbornene -amino acid unit into peptides and pseudopeptides, desymmetrization of diendonorbornene-2,3-dicarboxylic anhydride (25) with proline esters was applied, which contains a single conformationally constrained amino acid residue. As key step, a Curtius rearrangement was used to generate isocyanate 127, which reacted with protected amino acids and peptides to give oligopeptides 128 and 129 (Scheme 38) [13].

2. Gly-OMe O

O NH NHBoc 117: X = CH2 118: X = O

COOMe


BocHN

COOMe

BocHN

1. LiOH, MeOH 2. SOCl2, CH2Cl2

O

1. i-Pr2NEt 2. TFA 3. MeOCOCl

119: diexo 1. K2CO3, MeOH 2. TFA TFA . H2N


COCl O

120 5. MeNH2, HATU O

O

4. LiOH

COOMe

183

O

NH MeO

O

NH O

NH Me

O

122

121 O

O

O

NH RO

NH O

O NH

O

123

NH Me

O

R = t-Bu, Me

Scheme 34.

1. EDCI, HOBt H2Cl2 H2N

Me Me

2. DIPEA

COOMe

O

Me

NH O

diexo

OMe

NH O

O

n

2S,3R and 2R,3S isomers

n = 1, 2, 3

124

125

Scheme 35.

O

Dihedral angles for norbornane residue (Balaram's convention)

O H N

H N

O

BocNHN

H

Scheme 36.

H

H

Scheme 37.

O

NH

COOH

Et3N

O 25

COOR

126

O R = Me, t-Bu

O

NH ProOR

1. EtOCOCl Et3N, NaN3 2. benzene reflux

Z-Leu-Ala-Pro-OH

NH Pro-Ala-Leu-Z O 129

1. TFA 2. H-Phe-Gly-OMe EDC, HOBt

NH Pro-Phe-Gly-OMe

H

N C O 127

O

NH ProOR

Et3N,

NH Pro-Ala-Leu-Z

128

O

NH ProOR

Scheme 38.

For 129, conformational NMR and X-ray analysis showed that the pseudopeptide adopted a parallel -sheet conformation, and the parallel -sheet was stabilized by the formation of two intra-

molecular hydrogen bonds involving the NH groups of the alanine and valine residues [13].


Csende et al.

ACKNOWLEDGMENT The authors are indebted to Mrs. E. Csiszár-Makra for the typing of the manuscript.

[38]

REFERENCES

[40]

[1]

[41]

[2] [3] [4] [5]

[6] [7] [8]

[9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]

[21]

[22] [23]

[24] [25] [26] [27] [28] [29]

[30] [31] [32] [33] [34] [35] [36] [37]

Aguilar, M.; Purcell, A. W.; Devi, R.; Lew, R.; Rossjohn, J.; Smith, A. I.; Perlmutter, P. Org. Biomol. Chem., 2007, 5, 2884. Fülöp, F. Chem. Rev., 2001, 101, 2181. Fülöp, F.; Martinek, T. A.; Tóth, G. K. Chem. Soc. Rev., 2006, 35, 323. Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev., 2001, 101, 3219. Tóth, G.; Keresztes, A.; Tömböly, C.; Péter, A.; Fülöp, F.; Tourwé, D.; Navratilova, E.; Varga, É.; Roeske, W. R.; Yamamura, H. I.; Szcs, M.; Borsodi, A. Pure Appl. Chem., 2004, 76, 951. Miller, J. A.; Nguyen, S. T. Mini-Rev. Org. Chem., 2005, 2, 39. Kuhl, A.; Hahn, M. G.; Dumi, M.; Mittendorf, J. Amino Acids, 2005, 29, 89. Margetic, D.; Butler, D. N.; Warrener, R. N. The 9th Electronic Computational Chemistry Conference, (ECCC9), http://eccc9. cooper.edu, March 1-31, 2003, P95-1. Bernáth, G. Acta Chim. Hung., 1992, 129, 107. Stájer, G.; Csende, F.; Fülöp, F. Curr. Org. Chem., 2003, 7, 1423. Bernáth, G.; Stájer, G.; Fülöp, F.; Sohár, P. J. Heterocycl. Chem., 2000, 37, 439. Bernáth, G.; Fülöp, F.; Stájer, G. Janssen Chim. Acta, 1991, 9, 12. Hibbs, D. E.; Hursthouse, M. B.; Jones, I. G.; Jones, W.; Malik, K. M. A.; North, M. J. Org. Chem., 1998, 63, 1496. Jones, I. G.; Jones, W.; North, M. J. Org. Chem., 1998, 63, 1505. Jones, I. G.; North, M. Lett. Pept. Sci., 1998, 5, 171. Seebach, D.; Matthews, J. L. Chem. Commun., 1997, 2015. DeGrado, W. F.; Schneider, J. P.; Hamuro, Y. J. Pept. Res., 1999, 54, 206. Christianson, L. A.; Lucero, M. J.; Appella, D. H.; Klein, D. A.; Gellman, S. H. J. Comput. Chem., 2000, 21, 763. Hruby, V. J.; Li, G.; Haskell-Luevano, C.; Shenderovich, M. Pept. Sci., 1997, 43, 219. Lynch III, J. J.; Honore, P.; Anderson, D. J.; Bunnelle, W. H.; Mortell, K. H.; Zhong, C.; Wade, C. L.; Zhu, C. Z.; Xu, H.; Marsh, K. C.; Lee, C.-H.; Jarvis, M. F.; Gopalakrishnan, M. Pain, 2006, 125, 136. Chang, L. L.; Troung, Q.; Doss, G. A.; MacCoss, M.; Lyons, K.; McCauley, E.; Mumford, R.; Forrest, G.; Vincent, S.; Schmidt, J. A.; Hagmann, W. K. Bioorg. Med. Chem. Lett., 2007, 17, 597. Marcin, L. R.; Higgins, M. A. US 2005, 50113442; Chem. Abstr., 2005, 142, 481832. Levin, J. I.; Li, Z.; Diamantidis, G.; Lovering, F. E.; Wang, W.; Condon, J. S.; Lin, Y.; Skotnicki, J. S.; Park, K. US 2006, 211730; Chem. Abstr., 2006, 145, 356664. Ohtani, M.; Matsuura, T.; Watanabe, F.; Narisada, M. J. Org. Chem., 1991, 56, 2122. Ohtani, M.; Narisada, M. J. Med. Chem., 1990, 33, 1027. Honma, T. WO 1999, 99155027 A1; Chem. Abstr., 1999, 130, 252242. Ohtani, M.; Matsuura, T.; Shirahase, K. EP Appl. 1991, 453960 A1; Chem. Abstr., 1992, 116, 58988. Shen, T.-Y.; Harman, W. D.; Huang, D. F.; Gonzalez, J. WO 1994, 9422868 A1; Chem. Abstr., 1995, 123, 111844. Whiska, D. G.; Myers, J. K.; Rogers, B. N.; Jacobsen, E. J.; Piotrowsky, D. W.; Corbett, J. W.; Bodnar, A. L.; Groppi, V. E. Jr. WO 2003, 018585 A1; Chem. Abstr., 2003, 138, 204939. Shen, T.-Y.; Harman, W. D.; Huang, D. F.; Gonzalez, J. US 1998, 5817679; Chem. Abstr., 1998, 129, 276081. Rasmussen, J. K.; Hassner, A. Chem. Rev., 1976, 76, 389. Dhar, D. N.; Murthy, K. S. K. Synthesis, 1986, 437. Moriconi, E. J.; Crawford, W. C. J. Org. Chem., 1968, 33, 370. Mazzocchi, P. H.; Halchak, T.; Tamburin, H. J. J. Org. Chem., 1976, 41, 2808. Stájer, G.; Mód, L.; Szabó, A. E.; Fülöp, F.; Bernáth, G.; Sohár, P. Tetrahedron, 1984, 40, 2385. Forró, E.; Fülöp, F. Tetrahedron Asymmetry, 2004, 15, 573. Craig, D. J. Am. Chem. Soc., 1951, 73, 4889.

[39]

[42] [43]

[44] [45] [46] [47]

[48] [49] [50] [51]

[52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76]

Pandey, B.; Dalvi, P. V. Angew. Chem. Int. Ed. Engl., 1993, 32, 1612. Stájer, G.; Miklós, F.; Kanizsai, I.; Csende, F.; Sillanpää, R.; Sohár, P. Eur. J. Org. Chem., 2004, 3701. Stájer, G.; Virág, M.; Szabó, A. E.; Bernáth, G.; Sohár, P.; Sillanpää, R. Acta Chem. Scand., 1996, 50, 922. Palkó, M.; Sándor, E.; Sohár, P.; Fülöp, F. Monatsh. Chem., 2005, 136, 2051. Kotsuki, H.; Kitagawa S.; Nishizawa, H.; Tokoroyama, T. J. Org. Chem., 1978, 43, 1471. Kotsuki, H.; Nishizawa, H.; Kitagawa, S.; Ochi, M.; Yamasaki, N.; Matsuoka, K.; Tokoroyama, T. Bull. Chem. Soc. Jpn., 1979, 52, 544. Cordone, R.; Harman, W. D.; Taube, H. J. Am. Chem. Soc., 1989, 111, 5969. Akssira, M.; Dahdouh, A.; Kasmi, H. Bull. Soc. Chim. Belg., 1993, 102, 227. Canonne, P.; Akssira, M.; Dahdouh, A.; Kasmi, H.; Boumzebra, M. Tetrahedron, 1993, 49, 1985. Lieb, F.; Oediger, H.; Boeshagen, H.; Rosentreter, U.; Niewoehner, U.; Hoever, P.; Perzborn, E.; Seuter, F.; Fiedler, V. B. Ger. 1989, 3720760; Chem. Abstr., 1989, 111, 133793. Arai, Y.; Kawanami, S.; Koizumi, T. J. Chem. Soc., Perkin Trans. 1, 1991, 2969. Bolm, C.; Schiffers, I.; Dinter, C. L.; Defrère, L.; Gerlach, A.; Raabe, G. Synthesis, 2001, 1719. Bolm, C.; Schiffers, I.; Atodiresei, I.; Hackenberger, C. P. R. Tetrahedron Asymmetry, 2003, 14, 3455. Uray, G.; Bergt, C. 4th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-4), September 1-30, 2000, A0097. Bauer, L.; Miarka, S. V. J. Org. Chem., 1959, 24, 1293. Neumann, U.; Gütschow, M. J. Biol. Chem., 1994, 269, 21561. Just, G.; Martel, A. Tetrahedron Lett., 1973, 1517. Grieco, P. A.; Zabrowski, D. L.; Lis, R.; Finn, J. J. Org. Chem., 1984, 49, 1454. Masesane, I. B.; Steel, P. G. Synlett, 2003, 735. Shin, C.; Kosuge, Y.; Yamaura, M.; Yoshimura, J. Bull. Chem. Soc. Jpn., 1978, 51, 1137. Caputo, F.; Clerici, F.; Gelmi, M. L.; Nava, D.; Pellegrino, S. Tetrahedron, 2006, 62, 1288. Shin, C.; Narukawa, H.; Yamaura, M.; Yoshimura, J. Tetrahedron Lett., 1977, 18, 2147. Buñuel, E.; Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron Asymmetry, 1996, 7, 1521. Zhang, C.; Trudell, M. L. J. Org. Chem., 1996, 61, 7189. Stájer, G.; Szabó, A. E.; Fülöp, F.; Bernáth, G.; Sohár, P. Chem. Ber., 1987, 120, 259. Stájer, G.; Szabó, A. E.; Fülöp, F.; Bernáth, G. Synthesis, 1984, 345. Stájer, G.; Szabó, A. E.; Sohár, P.; Szúnyog, J.; Bernáth, G. Synthesis, 1998, 718. Stájer, G.; Szabó, A. E.; Csámpai, A.; Sohár, P. Eur. J. Org. Chem., 2004, 1318. Stájer, G.; Szabó, A. E.; Fülöp, F.; Bernáth, G.; Sohár, P. J. Chem. Soc., Perkin Trans. 1, 1985, 2483. Fülöp, F.; Huber, I.; Szabó, Á.; Bernáth, G.; Sohár, P. Tetrahedron, 1991, 47, 7673. Stájer, G.; Szabó, A. E.; Bernáth, G. J. Chem. Soc., Perkin Trans. 1, 1987, 237. Frimpong-Manso, S.; Nagy, K.; Stájer, G.; Bernáth, G.; Sohár, P. J. Heterocycl. Chem., 1992, 29, 221. Stájer, G.; Szabó, A. E.; Sohár, P. Heterocycles, 1999, 51, 1849. Stájer, G.; Szabó, A. E.; Fülöp, F.; Bernáth, G.; Sohár, P. J. Heterocycl. Chem., 1983, 20, 1181. Stájer, G.; Szabó, A. E.; Fülöp, F.; Bernáth, G.; Sohár, P. J. Heterocycl. Chem., 1984, 21, 1373. Sohár, P.; Stájer, G.; Nagy, K.; Bernáth, G. Magn. Reson. Chem., 1995, 33, 329. Stájer, G.; Virág, M.; Sillanpää, R. Acta Cryst. C, 1999, 55, 1342. Virág, M.; Günther, G.; Böcskei, Z.; Sohár, P.; Bernáth, G.; Stájer, G. J. Mol. Struct., 1998, 440, 147. Sillanpää, R.; Stájer, G.; Pihlaja, K. Acta Chem. Scand., 1994, 48, 84.

Chemistry of Norbornane/ene and Heteronorbornane/ene -Amino Acids [77] [78] [79] [80] [81] [82] [83]

Sohár, P.; Miklós, F.; Csámpai, A.; Stájer, G. J. Chem. Soc., Perkin Trans. 1, 2001, 558. Miklós, F.; Stájer, G.; Sohár, P.; Böcskei, Z. Synlett, 2000, 67. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed., 2000, 39, 3169. Gedey, S.; Eycken, J. V.; Fülöp, F. Org. Lett., 2002, 4, 1976. Basso, A.; Banfi, L.; Riva, R.; Guanti, G. Tetrahedron Lett., 2004, 45, 587. Kanizsai, I.; Szakonyi, Z.; Sillanpää, R.; Fülöp, F. Tetrahedron Lett., 2006, 47, 9113. Kanizsai, I.; Gyónfalvi, S.; Szakonyi, Z.; Sillanpää, R.; Fülöp, F. Green Chem., 2007, 9, 357.

Received: November 1, 2007

Current Organic Synthesis, 2008, Vol. 5, No. 2 [84] [85]

[86]

[87]

185

Doerksen, R. J.; Chen, B.; Yuan, J.; Winkler, J. D.; Klein, M. L.; Chem. Commun., 2003, 2534. Chandrasekhar, S.; Babu, B. N.; Prabhakar, A.; Sudhakar, A.; Reddy, M. S.; Kiran, M. U.; Jagadeesh, B. Chem. Commun., 2006, 1548. Chandrasekhar, S.; Reddy, M. S.; Jagadeesh, B.; Prabhakar, A.; Rao, M. H. V. R.; Jagannadh, B. J. Am. Chem. Soc., 2004, 126, 13586. Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem. Rev., 2001, 101, 3131.

Revised: December 5, 2007

Accepted: January 11, 2008