)JOEBXJ1VCMJTIJOH$PSQPSBUJPO +PVSOBMPG$IFNJTUSZ …downloads.hindawi.com/journals/jchem/2016/1504682.pdf · trans --hydroxy-L-proline. e Friedl ¨ander condensation between -amino-substituted

Research ArticleAn Unprecedented Straightforward Synthesis ofChiral Pyrrolo[34-b]quinolone and Pyrrolo[32-b]quinoloneBackbones Starting from trans-4-Hydroxy-L-proline

Seacutebastien Comesse and Adam Dach

Laboratoire de Chimie URCOM EA 3221 FR CNRS 3038 Normandie Universite Universite du HavreUFR Sciences et Techniques 25 rue Philippe Lebon 76058 Le Havre Cedex France

Correspondence should be addressed to Sebastien Comesse sebastiencomesseuniv-lehavrefr

Received 2 November 2015 Accepted 29 December 2015

Academic Editor Marco Radi

Copyright copy 2016 S Comesse and A Daıch This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The straightforward synthesis of pyrrolo[34-b]quinolone andpyrrolo[32-b]quinolone backbones which can be found inmoleculesexhibiting anticancer activities is presentedThe key step of the process is an efficient and unprecedented Friedlander condensationbetween an oxoproline carbamate obtained in 3 steps and good yield starting from commercially available and relatively cheaptrans-4-hydroxy-L-proline and various 2-amino-substituted carbonyl derivatives It was demonstrated that the formation of thetwo possible regioisomers was fully triggered by both the R substituent onto the 2-amino-substituted carbonyl compounds and theester function onto the oxoproline carbamate Thus in some cases a complete regiocontrol for the Friedlander reaction could beattained

1 Introduction

Natural or synthetic N-heterocyclic compounds containinga condensed quinoline ring system continue to attract theinterest of both organic and medicinal chemists mostly dueto their antitumor activities [1 2] Among them pyrrolo[34-b]quinolone I and pyrrolo[32-b]quinolone II are two back-bones of important value which can be found in moleculesof high biological interest (Figure 1) Indeed pyrrolo[34-b]quinolone I is a key constituent of the alkaloid camp-tothecin (CPT 1) selective poison of DNA topoisomerase 1and thus well known for its anticancer activities Over theyears the synthesis or isolation of many analogues of CPTpossessing a pyrrolo[34-b]quinolone backbone togetherwith their biological evaluation has been published [3]For example the alkaloids luotonin A (2a) and rosettacin(2b) belonging to the aromathecin family were proved toexhibit important cytotoxicity demonstrating once again thegreat interest of this skeleton [4] Pyrrolo[32-b]quinolonemoiety II is the central core of the alkaloid cryptolepine(3) traditionally used as an antimalarial drug [5 6] It was

shown that this alkaloid was able to intercalate with DNAprompting it as a potential chemotherapeutic agent [7]Compounds 4 have been published recently and were testedsuccessfully over different cancer types highlighting theirbiological potential [8]

Interested for many years in the synthesis of aromath-ecins we have devoted a lot of efforts for the developmentof short and efficient routes for the access to these skeletons[9 10] Recently we have shown that the total synthesis ofrosettacin (2b) could be achieved in few steps using an arylradical cyclization onto an enamide [11]

In this paper the unprecedented access to bothpyrrolo[34-b]quinolone and pyrrolo[32-b]quinolone back-bones 5 and 6 starting from oxoproline carbamate 8 usingFriedlander reaction for the formation of the C ring isdiscussed (see lower part of Scheme 1) It is important tonotice that very interesting works were published employingthe Friedlander reaction for the synthesis of pyrrolo[34-b]quinolone andor pyrrolo[32-b]quinolone backbones[12 13] Nevertheless to the best of our knowledge this is thefirst time that this reaction is used with oxoproline carbamate

Hindawi Publishing CorporationJournal of ChemistryVolume 2016 Article ID 1504682 5 pageshttpdxdoiorg10115520161504682

2 Journal of Chemistry

NN

O

O

OHO

N

N

Me

NNH

NH

N

NH

N

N

NN

X

O

NH

N

R

This paper

N

Backbones of interest

4

5

6

A B C

A B C

Camptothecin 1

Cryptolepine 3

R1O

R1O

R2

CO2Bn

CO2Bn

X = N luotonin A 2aX = CH rosettacin 2b

Pyrrolo[34-b]quinoline I

Pyrrolo[32-b]quinoline II

N-Heterocycles with anticancer activity

Figure 1 Interest of pyrrolo[34-b]quinolone and pyrrolo[32-b]quinolone backbones I and II

N

O

Boc

X

RN

N

RNN

5 6

+ andor

7 8

NO

Previous work

This work

X

R

X

N

XN

NO

NN N

N

R

Boc

Boc

X

R

R

R

Role on the regiocontrol

NH2

NH2

R1

R1 R1

R1

R1

CO2R2 CO2R2

Ref [12]

Ref [13]

Friedlaumlnderreaction



NH2

+

++

CO2Bn

CO2Bn CO2Bn

R ne H complete regiocontrol

Scheme 1 Known strategies for the synthesis of pyrrolo[34-b]quinolone and pyrrolo[32-b]quinolone backbones and our retrosyntheticpathway to products 5 and 6

8 in order to study the influence of the ester function ontothe regioselectivity of the process In fact we have shownthat the formation of regioisomers 5 andor 6 was triggeredby both the R substituent onto 7 and the ester functiononto 8 Indeed when R group is not a hydrogen atom onlyregioisomers 6 were obtained in good yield demonstratingthe dramatic role of these two groups Moreover besidesthe biological interest of the scaffolds 5 and 6 the access tothese new proline derivatives could be of great importancein organocatalysis chemistry

2 Materials and Methods

21 General Remarks All commercially available startingmaterials were purchased from the Aldrich Chemical Co or

Acros Organics Co and were used without further purifi-cation Solvents were dried when necessary by standardmethods All reactions were carried out under argon Theprogress of the reactions was monitored by thin layer chro-matography (TLC) Thin layer chromatography (TLC) wasperformed using silica gel analytical plates (F254) of 025mmthickness The detection on TLC plates was performed byUV light at 254 or 365 nm or using a permanganate orp-anisaldehyde revelator Compositions of stereoisomericmixtures were determined by 1H NMR analysis of the crudemixture before any purification Melting points (Mp) weretakenwith a SMP10 capillarymelting point apparatus (Stuart)and are uncorrected The NMR spectra were recorded assolutions in CDCl

3at 200MHz (1H) and 50MHz (13C)

respectively and chemical shifts (120575) are expressed in ppm

Journal of Chemistry 3

NH

HO

N

Boc Boc

N

O

10 44 (2 steps) 8 789

CO2Bn CO2BnCO2H

HO

Scheme 2 Synthesis of oxoproline carbamate 8

N

O

Boc

X

NH

N

NH

N

79 (2 steps)

R

R

R

(1)

NH

N

NH

N

NH

N

NH

N

Me Ph

8

7

5 6

6a

5a

N

7a

O

Me7b

O

Ph7c

PTSA (cat)

CO2Bn

CO2Bn CO2Bn CO2Bn

CO2Bn

CO2Bn

CO2BnCF3CO2H(2)

NH2

NH2 NH2 NH2

+

6b 63 (2 steps) 6c 58 (2 steps)

= 30 706a 5a

Scheme 3 Access to pyrrolo[34-b]- and pyrrolo[32-b]quinolone derivatives 5 and 6

The assignments for compounds 8 and 10 matched thosepreviously published [14]

22 General Procedure for the Synthesis of Compounds 5 and6 The required aniline derivative 7 (055mmol 11 eq) andoxoproline carbamate 8 (160mg 05mmol 1 eq) were dis-solved in freshly distilled toluene (5mL) p-Toluenesulfonicacid (PTSA 95mg 005mmol 01 eq) was then addedThe mixture was stirred under reflux for 14 hours and thesolvent was removed under vacuum The crude mixture wasdissolved in EtOAc (20mL) andwas thenwashed successivelywith a saturated aqueous solution of NaHCO

3(10mL) and

brine (10mL) The organic layer was dried over MgSO4and

concentrated under vacuum The crude mixture was directlyused in the next step without further purification

The crude of the previous step was dissolved in freshlydistilled CH

2Cl2

(5mL) and trifluoroacetic acid (TFA037mL 10 eq) was then added After one night of stirring atroom temperature the solvent was removed under vacuumThe crude mixture was dissolved in EtOAc (20mL) and wasthen washed successively with a saturated aqueous solutionof NaHCO

3(2 lowast 10mL) and brine (10mL)The organic layer

was dried over MgSO4and concentrated under vacuumThe

residuewas then chromatographed on silica gel to provide thedesired compound (typically AcOEtcyclohexane 20 80)

3 Results and Discussion

The key oxoproline carbamate 8 was synthesized startingfrom commercially available trans-4-hydroxy-L-proline (9)using a modified version of the route reported by Qiuand Qing (Scheme 2) [14] Starting material (9) was firstconverted in two steps that is Boc protection of the nitro-gen atom and benzylation of the acid function into thecorresponding N-Boc-benzyl ester 10 in 44 overall yieldOxidation of the alcohol moiety was performed using PCCand led to the desired product 8 in a good 78 yield

Friedlander condensations between oxoprolinecarbamate 8 and aniline derivatives 7 were carried out usingclassical procedure (Scheme 3) [15] In order to facilitate theNMR spectra analysis the Friedlander reaction was directlyfollowed by Boc deprotection of the nitrogen atom of thepyrrolidine ring using trifluoroacetic acid In the case of 7a(see lower part of Scheme 3) the two regioisomers 5a and 6awere formed in a good 79 yield and in a 70 30 ratio Thisregioselectivity is in accordance with the one observed by


N

O

8

5 6

O

R7

N

NH

RO

N

NR

N

N

ROH

OH

13

12

14

11

N

HN

Boc

Boc

BocBoc

Boc

R

O(1) PTSA

CO2Bn

CO2BnCO2Bn

CO2BnCO2Bn+ +

NH2

CF3CO2H(2) CF3CO2H(2)

Scheme 4 Proposed mechanism for the Friedlander reaction leading to 5 and 6

Akue-Gedu and coworkers for similar substrate [13]Interestingly when substrates 7b and 7c were employed onlyregioisomers 6b and 6c were observed by 1H NMR of thecrude mixture prior to any purification They were isolatedafter chromatographic purification in 63 and 58 yieldrespectively

The unprecedented high regioselectivity in favour ofproducts 6 is not fully understood yet Nevertheless based onthemechanism commonly accepted for the Friedlander reac-tion [15] we propose the following mechanism (Scheme 4)In the presence of p-toluenesulfonic acid (PTSA) startingmaterials 7 and 8 led to the formation of the two possibleenamines 11 and 12 in equilibrium with the correspondingtricyclic compounds 13 and 14 The observed regioselectivitycould result from the steric hindrance and interactionsbetween the R group and the ester function in intermediate 13versus the R group and the Boc function in intermediate 14This hypothesis will have to be confirmed by a computationalanalysis Finally when R = H intermediate 14 was favouredand led to 6 by loss of water and Boc deprotection

The structure of product 5a was deduced from its 1HNMR and 13C NMR spectral data and by comparison withsimilar structures [12 13] For example the 1H NMR spec-trum of 5a contained two doublets (120575 = 464 and 440 ppm119869 = 157Hz) for the two CH

2protons of the pyrrolidine ring

confirming the presence of a stereogenic center

(S)-Benzyl 23-Dihydro-1H-pyrrolo[34-b]quinoline-1-carbox-ylate (5a) This product was obtained by reaction between 8and 7a 54 over 2 steps (AcOEtcyclohexane 20 80) 1HNMR (200MHz CDCl

3) 820ndash812 (m 2H) 776ndash765 (m

2H) 755ndash747 (m 1H) 737 (bs 5H) 532ndash519 (m 3H) 464(d 119869 = 157Hz 1H) 440 (d 119869 = 157Hz 1H) 236 (bs 1H) 13CNMR (50MHz CDCl

3) 1718 1636 1484 1351 1309 1297

1287 1284 1280 1270 1262 676 636 524

Moreover 5a13CDEPT-135 NMR spectrum showed boththe presence of the carbonyl carbon at 120575 = 1718 ppm and

the CH and CH2carbons of the pyrrolidine ring at 636 and

524 ppm respectively In the case of the 1H NMR spectrumfor products 6 they all displayed the same characteristicdoublet of doublet for the two CH

2and CH proton of

the pyrrolidine ring For example compound 6b exhibits adoublet of doublet (119869 = 94 and 55Hz) for the CH at 458 ppmand two doublet of doublet (119869 = 180 and 94Hz and 119869 = 180and 55Hz) at 368 and 354 ppm respectively

(S)-Benzyl 9-Methyl-23-dihydro-1H-pyrrolo[32-b]quinoline-2-carboxylate (6b) This product was obtained by reactionbetween 8 and 7b 63 over 2 steps (AcOEtcyclohexane20 80) 1HNMR (200MHz CDCl

3) 792ndash785 (m 1H) 783ndash

775 (m 1H) 749ndash740 (m 2H) 736 (bs 5H) 520 (s 2H)459 (bs 1H) 458 (dd 119869 = 94 and 55Hz 1H) 368 (dd 119869 =180 and 94Hz 1H) 354 (dd 119869 = 180 and 55Hz 1H) 242(s 3H) 13C NMR (50MHz CDCl

3) 1733 1543 1438 1399

1352 1290 1288 1287 1284 1261 1254 1223 1176 676578 357 121 [120572]D

20 + 192 (119888 = 061 CHCl3)

Finally its 13C DEPT-135 NMR spectrum also confirmedthe presence of the carbonyl carbon at 120575 = 1733 ppm whenthe CH and CH

2carbons were observed at 578 and 357 ppm

respectively

4 Conclusion

The regioselective access to both pyrrolo[34-b]quinoloneand pyrrolo[32-b]quinolone backbones was achieved in 5steps and good yield starting from commercially availabletrans-4-hydroxy-L-proline The Friedlander condensationbetween 2-amino-substituted carbonyl compounds and anoxoproline carbamatewas efficient and allowed the formationof the desired products in good yield More importantlyand to the best of our knowledge this is the first timethat this reaction between these two partners was stud-ied We have shown that the access to the two possibleregioisomers was controlled by both the R substituent onto


the 2-amino-substituted carbonyl derivatives and the esterfunction of the oxoproline carbamate This synthetic strategycould be used in the future to regioselectively access either thepyrrolo[34-b]quinolone or pyrrolo[32-b]quinolone back-bones by modulating substituents onto Friedlander reactionrsquospartnersThis reactivity is already under investigation and theresults will be published in due course

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors thank the ldquoFederation de Chimierdquo FR CNRS3038 (INC3M) the ldquoreseau CRUNCHrdquo and the URCOMlaboratory for their financial support

References

[1] C Karthikeyan C Lee J Moore et al ldquoIND-2 a pyr-imido[110158401015840211015840101584015]pyrazolo[34-b]quinoline derivative circum-vents multi-drug resistance and causes apoptosis in coloncancer cellsrdquo Bioorganic amp Medicinal Chemistry vol 23 no 3pp 602ndash611 2015

[2] D B Khadka and W-J Cho ldquo3-Arylisoquinolines as noveltopoisomerase i inhibitorsrdquo Bioorganic and Medicinal Chem-istry vol 19 no 2 pp 724ndash734 2011

[3] Y Pommier ldquoDNA topoisomerase I inhibitors chemistrybiology and interfacial inhibitionrdquo Chemical Reviews vol 109no 7 pp 2894ndash2902 2009

[4] M A Cinelli A E Morrell T S Dexheimer et al ldquoThestructurendashactivity relationships of A-ring-substitutedaromathecin topoisomerase I inhibitors strongly supporta camptothecin-like binding moderdquo Bioorganic and MedicinalChemistry vol 18 no 15 pp 5535ndash5552 2010

[5] O Onyeibor S L Croft H I Dodson et al ldquoSynthesis ofsome cryptolepine analogues assessment of their antimalarialand cytotoxic activities and consideration of their antimalarialmode of actionrdquo Journal of Medicinal Chemistry vol 48 no 7pp 2701ndash2709 2005

[6] C W Wright J Addae-Kyereme A G Breen et al ldquoSynthesisand evaluation of cryptolepine analogues for their potential asnew antimalarial agentsrdquo Journal of Medicinal Chemistry vol44 no 19 pp 3187ndash3194 2001

[7] K Bonjean M C De Pauw-Gillet M P Defresne et alldquoThe DNA intercalating alkaloid cryptolepine interferes withtopoisomerase II and inhibits primarily DNA synthesis in B16melanoma cellsrdquo Biochemistry vol 37 no 15 pp 5136ndash51461998

[8] H-J Kim M I El-Gamal Y S Lee and C-H Oh ldquoSynthesisand preliminary cytotoxicity evaluation of new diarylamidesand diarylureas possessing 23-dihydropyrrolo[32-b]quinolinescaffoldrdquo Bulletin of the Korean Chemical Society vol 34 no 8pp 2480ndash2486 2013

[9] F Pin S Comesse M Sanselme and A Daıch ldquoA dominoN-amidoacylationaldol-type condensation approach to thesynthesis of the topo-I inhibitor rosettacin and derivativesrdquoJournal of Organic Chemistry vol 73 no 5 pp 1975ndash1978 2008

[10] F Pin S Comesse andA Daıch ldquoAssociation of intramolecularfuran Diels-Alder reaction and N-acyliminium alkylation forthe synthesis of pentacyclic precursor of aromathecinsrdquo Synlettpp 3214ndash3218 2009

[11] L El Blidi A Namoune A Bridoux et al ldquoExpeditioussynthesis of the topoisomerase I inhibitors isoindolo[21-b]isoquinolin-7(5H)-one and the alkaloid rosettacin based onaryl radical cyclization of enamide generated by using N-acyliminium chemistryrdquo Synthesis vol 47 no 22 pp 3583ndash3592 2015

[12] T Brunin L Legentil J-P Henichart and B Rigo ldquoTowardsnew camptothecins Part 3 synthesis of 5-methoxycarbonylcamptothecinrdquoTetrahedron vol 62 no 17 pp 3959ndash3968 2006

[13] R Akue-Gedu P Gautret J-P Lelieur and B Rigo ldquoAnimproved synthesis of methyl 13-dihydro-2H-pyrrolo[34-b]quinoline-2-carboxylaterdquo Synthesis no 21 pp 3319ndash33222007

[14] X-L Qiu and F-L Qing ldquoPractical synthesis of Boc-protectedcis-4-trifluoromethyl and cis-4-difluoromethyl-L- prolinesrdquoJournal of Organic Chemistry vol 67 no 20 pp 7162ndash71642002

[15] J Marco-Contelles E Perez-Mayoral Abdelouahid SamadiM D C Carreiras and E Soriano ldquoRecent advances in theFriedlander reactionrdquo Chemical Reviews vol 109 no 6 pp2652ndash2671 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


NN

O

O

OHO

N

N

Me

NNH

NH

N

NH

N

N

NN

X

O

NH

N

R

This paper

N

Backbones of interest

4

5

6

A B C

A B C

Camptothecin 1

Cryptolepine 3

R1O

R1O

R2

CO2Bn

CO2Bn

X = N luotonin A 2aX = CH rosettacin 2b

Pyrrolo[34-b]quinoline I

Pyrrolo[32-b]quinoline II

N-Heterocycles with anticancer activity

Figure 1 Interest of pyrrolo[34-b]quinolone and pyrrolo[32-b]quinolone backbones I and II

N

O

Boc

X

RN

N

RNN

5 6

+ andor

7 8

NO

Previous work

This work

X

R

X

N

XN

NO

NN N

N

R

Boc

Boc

X

R

R

R

Role on the regiocontrol

NH2

NH2

R1

R1 R1

R1

R1

CO2R2 CO2R2

Ref [12]

Ref [13]




NH2

+

++

CO2Bn

CO2Bn CO2Bn

R ne H complete regiocontrol

Scheme 1 Known strategies for the synthesis of pyrrolo[34-b]quinolone and pyrrolo[32-b]quinolone backbones and our retrosyntheticpathway to products 5 and 6

8 in order to study the influence of the ester function ontothe regioselectivity of the process In fact we have shownthat the formation of regioisomers 5 andor 6 was triggeredby both the R substituent onto 7 and the ester functiononto 8 Indeed when R group is not a hydrogen atom onlyregioisomers 6 were obtained in good yield demonstratingthe dramatic role of these two groups Moreover besidesthe biological interest of the scaffolds 5 and 6 the access tothese new proline derivatives could be of great importancein organocatalysis chemistry

2 Materials and Methods

21 General Remarks All commercially available startingmaterials were purchased from the Aldrich Chemical Co or

Acros Organics Co and were used without further purifi-cation Solvents were dried when necessary by standardmethods All reactions were carried out under argon Theprogress of the reactions was monitored by thin layer chro-matography (TLC) Thin layer chromatography (TLC) wasperformed using silica gel analytical plates (F254) of 025mmthickness The detection on TLC plates was performed byUV light at 254 or 365 nm or using a permanganate orp-anisaldehyde revelator Compositions of stereoisomericmixtures were determined by 1H NMR analysis of the crudemixture before any purification Melting points (Mp) weretakenwith a SMP10 capillarymelting point apparatus (Stuart)and are uncorrected The NMR spectra were recorded assolutions in CDCl

3at 200MHz (1H) and 50MHz (13C)

respectively and chemical shifts (120575) are expressed in ppm


NH

HO

N

Boc Boc

N

O

10 44 (2 steps) 8 789

CO2Bn CO2BnCO2H

HO


N

O

Boc

X

NH

N

NH

N

79 (2 steps)

R

R

R

(1)

NH

N

NH

N

NH

N

NH

N

Me Ph

8

7

5 6

6a

5a

N

7a

O

Me7b

O

Ph7c

PTSA (cat)

CO2Bn

CO2Bn CO2Bn CO2Bn

CO2Bn

CO2Bn

CO2BnCF3CO2H(2)

NH2

NH2 NH2 NH2

+

6b 63 (2 steps) 6c 58 (2 steps)

= 30 706a 5a




3(10mL) and




2Cl2









N

O

8

5 6

O

R7

N

NH

RO

N

NR

N

N

ROH

OH

13

12

14

11

N

HN

Boc

Boc

BocBoc

Boc

R

O(1) PTSA

CO2Bn

CO2BnCO2Bn

CO2BnCO2Bn+ +

NH2









3) 820ndash812 (m 2H) 776ndash765 (m


3) 1718 1636 1484 1351 1309 1297

1287 1284 1280 1270 1262 676 636 524




2and CH proton of





3) 1733 1543 1438 1399

1352 1290 1288 1287 1284 1261 1254 1223 1176 676578 357 121 [120572]D

20 + 192 (119888 = 061 CHCl3)



respectively

4 Conclusion






Acknowledgments


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


NH

HO

N

Boc Boc

N

O

10 44 (2 steps) 8 789

CO2Bn CO2BnCO2H

HO


N

O

Boc

X

NH

N

NH

N

79 (2 steps)

R

R

R

(1)

NH

N

NH

N

NH

N

NH

N

Me Ph

8

7

5 6

6a

5a

N

7a

O

Me7b

O

Ph7c

PTSA (cat)

CO2Bn

CO2Bn CO2Bn CO2Bn

CO2Bn

CO2Bn

CO2BnCF3CO2H(2)

NH2

NH2 NH2 NH2

+

6b 63 (2 steps) 6c 58 (2 steps)

= 30 706a 5a




3(10mL) and




2Cl2









N

O

8

5 6

O

R7

N

NH

RO

N

NR

N

N

ROH

OH

13

12

14

11

N

HN

Boc

Boc

BocBoc

Boc

R

O(1) PTSA

CO2Bn

CO2BnCO2Bn

CO2BnCO2Bn+ +

NH2









3) 820ndash812 (m 2H) 776ndash765 (m


3) 1718 1636 1484 1351 1309 1297

1287 1284 1280 1270 1262 676 636 524




2and CH proton of





3) 1733 1543 1438 1399

1352 1290 1288 1287 1284 1261 1254 1223 1176 676578 357 121 [120572]D

20 + 192 (119888 = 061 CHCl3)



respectively

4 Conclusion






Acknowledgments


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

O

8

5 6

O

R7

N

NH

RO

N

NR

N

N

ROH

OH

13

12

14

11

N

HN

Boc

Boc

BocBoc

Boc

R

O(1) PTSA

CO2Bn

CO2BnCO2Bn

CO2BnCO2Bn+ +

NH2









3) 820ndash812 (m 2H) 776ndash765 (m


3) 1718 1636 1484 1351 1309 1297

1287 1284 1280 1270 1262 676 636 524




2and CH proton of





3) 1733 1543 1438 1399

1352 1290 1288 1287 1284 1261 1254 1223 1176 676578 357 121 [120572]D

20 + 192 (119888 = 061 CHCl3)



respectively

4 Conclusion






Acknowledgments


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





Acknowledgments


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Documents

)JOEBXJ1VCMJTIJOH$PSQPSBUJPO +PVSOBMPG$IFNJTUSZ …downloads.hindawi.com/journals/jchem/2016/1504682.pdf · trans --hydroxy-L-proline. e Friedl ¨ander condensation between -amino-substituted