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�SYNTHETIC STUDIES OF EPIQUINAMIDE

By Chitlada Hemmara

A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree

Master of Science Program in Organic Chemistry

Department of Chemistry

Graduate School, Silpakorn University

Academic Year 2012

Copyright of Graduate School, Silpakorn University

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สมุดกลาง

SYNTHETIC STUDIES OF EPIQUINAMIDE

By Chitlada Hemmara

A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree

Master of Science Program in Organic Chemistry

Department of Chemistry

Graduate School, Silpakorn University

Academic Year 2012

Copyright of Graduate School, Silpakorn University



การศึกษาการสังเคราะห์ Epiquinamide

โดย นางสาวจิตรลดา เหมรา

วทิยานิพนธ์นีเป็นส่วนหนึงของการศึกษาตามหลกัสูตรปริญญาวทิยาศาสตรมหาบัณฑิต สาขาวชิาเคมีอนิทรีย์

ภาควชิาเคม ีบัณฑิตวทิยาลยั มหาวทิยาลยัศิลปากร

ปีการศึกษา 2555 ลขิสิทธิของบัณฑิตวทิยาลยั มหาวทิยาลยัศิลปากร



The Graduate School, Silpakorn University has approved and accredited the Thesis title of “Synthetic studies of epiquinamide” submitted by missChitlada Hemmara as a partial fulfillment of the requirements for the degree of Master of Science in Organic Chemistry

…………………………………………………….

(Assistant Professor Panjai Tantatsanawong,Ph.D.) Dean of Graduate School ........../................/.......... The Thesis Advisor Punlop Kuntiyong, Ph.D. The Thesis Examination Committee .................................................... Chairman (Assistant Professor Kanok-on Rayanil, Ph.D.) ............/................./.............. .................................................... Member (Associate Professor Boonsong Kongkathip, Ph.D.) ............/................./.............. .................................................... Member (Punlop Kuntiyong, Ph.D.) ............/.................../.............



iv

53302202 : MAJOR : ORGANIC CHEMISTRY KEY WORD : EPIQUINAMIDE/QUINOLIZIDINE ALKALOIDS/N-ACYLIMINIUM ION

CYCLIZATION CHITLADA HEMMARA : SYNTHETIC STUDIES OF EPIQUINAMIDE. THESIS ADVISOR : PUNLOP KUNTIYONG, Ph.D. 96 pp. Epiquinamide, a quinolizidine alkaloid isolated from the skin of the poisonous Ecuadorian frog Epidobates tricolor. Herein we report a synthesis of a dibenzylamino quinolizidinone which is the key intermediate in our synthetic approach toward epiquinamide. Our synthesis features highly diastereoselective N-acyl iminium ion cyclization as the key step. Dibenzylamine quinolizidinone intermediate was obtained from intramolecular cyclization of iminium ion formed in situ upon treatment of a corresponding N-3-butenyl hydroxylactam with a Lewis acid. The hydroxylactam was synthesized in 3 steps starting with amide formation of 3-butenylamine hydrochloride and a corresponding carboxylic acid. The carboxylic acid was prepared from (L)-Glutamic acid in 5 steps.

Department of Chemistry Graduate School, Silpakorn University Student's signature ........................................ Academic Year 2012 Thesis Advisor's signature ........................................



v

53302202 : สาขาวชิาเคมีอินทรีย ์คาํสาํคญั : อีพิควนิาไมด/์ควโินลิซิดีน แอลคาลอยด์/การปิดวงของ N-acyliminium ion จิตรลดา เหมรา : การศึกษาการสังเคราะห์ Epiquinamide อาจารยที์ปรึกษาวทิยานิพนธ์ : อ.ดร.พลัลภ คนัธิยงค.์ 96 หนา้. อีพิควนิาไมด ์เป็นอลัคาลอยดป์ระเภทควโินลิซิดีน แยกไดจ้ากผวิหนงัของกบมีพิษ Epidobates tricolor พบไดใ้นประเทศเอกวาดอร์ เริมแรกพบวา่ อีพิควนิาไมดมี์ฤทธิในการย ั บยงัการใชส้ารเสพติดประเภทนิโคติน และมีความจาํเพาะเจาะจงกบั α2 nicotinic acetyl-choline

esterase แต่ภายหลงัพบวา่ฤทธิดงักล่าวเป็นผลเนืองมาจากการปนเปือนของ สารอีพิบาทิดีน ในวทิยานิพนธ์นีบรรยายถึงการสังเคราะห์อีพิควนิาไมด ์โดยมี dibenzylamino quinolizidinone เป็นสารมธัยนัตห์ลกั และอาศยัปฏิกิริยาหลกัไดแ้ก่การปิดวงของ N-acyliminium ion ภาควชิาเคมี บณัฑิตวทิยาลยั มหาวทิยาลยัศิลปากร ลายมือชือนกัศึกษา........................................ ปีการศึกษา 2555 ลายมือชืออาจารยที์ปรึกษาวทิยานิพนธ์ ......................................



vi

ACKNOWLEDGEMENTS

I would like to express my appreciation to Dr. Punlop Kunthiyong, my advisor, for guidance, suggestion and supervision throughout my study.

I also would like to express my sincere gratitude to the committee member :

Associate Professor Dr. Boonsong Kongkathip, and Assistant Professor Dr. Kanok-on Rayanil for their comments and valuable opinions.

I would like to acknowledge my thanks to the department of Chemistry Silpakorn

University for Graduate fellowships and Thailand Research Fund for TRF-Master Research Grants.

Finally, this thesis will never be accomplished without my family’s care.



vii

Contents

Page English Abstract .................................................................................................................. iv Thai Abstract………………….………………………………………………………..... v Acknowledgements……………………………………………………………………… vi List of Figures ..................................................................................................................... viii List of Schemes……………………………………………...…………………………… ix Abbreviations…………………………………………………………………………….. xi Chapter 1 General Introduction……………………………………………...………….… 1 Isolation and structure elucidation……………………………………….. 5 Previous synthesis of epiquinamide……………………………………… 6 2 Total synthesis of epiquinamide……………………….…………………….... 17 3 General conclusion…………………………………………..……………….. 27 4 Experimental procedures………………………………………..………….… 28 References……………………………………………………………………………. 40 Appendix……………….………………...…………………………………………… 42 1H NMR and 13C NMR spectra of compounds……………….………...…….………. 43 Biography…………………………………………………………………………….. 96



viii

List of Figures

Figures Page 1.1 Structural type of selected alkaloids. .............................................................. 2 1.2 Structures of heterocyclic alkaloids of various structural types..................... 3 1.3 Structure type of quinolizidine alkaloids………………………………........... 4 1.4 Ecuadorain frog, Epidobates tricolor and structure of Epibatidine and Epiquinamide…………………………………………………………….. 5



ix

List of Scheme

Scheme Page 1.1 Blaauw ’s retrosynthetic analysis of epiquinamide.. ....................................... . 6 1.2 Blaauw ’s synthesis of the bicyclic core of epiquinamide............................... 7 1.3 Blaauw ’s completion of the synthesis of epiquinamide.…………………….. 8 1.4 Kanakubo’s synthesis of (±)-epiquinamide………………………………… 9 1.5 Gerwick’s retrosynthetic analysis of epiquinamide........................................... 10

1.6 Synthesis of mesylate 19…………................................................................ 11

1.7 Gerwick’s of epiquinamide …………..………………………………...…. 12

1.8 Ghosh’s retrosynthetic analysis of epiquinamide.………..……………….. 12

1.9 Ghosh’s synthesis of epiquinamide................................................................. 13

1.10 Chandrasekhar’s retrosynthetic analysis of (-)-epiquinamide ..……….….. 14

1.11 Chandrasekhar’s synthetic analysis of diol 44...............……………...….. 15

1.12 Chandrasekhar’s synthetic analysis of (-)-epiquinamide …………..……. 16

2.1 Retrosynthetic analysis of epiquinamide…………………………….….... 17 2.2 Synthesis of aldehyde 57………………………………………………… 18 2.3 Grignard reaction of aldehyde 57 with various Grignard reagent……..….. 18 2.4 Oxidation of vinyl alcohol 59……………………………………..………. 19 2.5 Attemp to synthesized diene 49………………………………………….. 19 2.6 Reduction of alkynyl alcohol 60…………………………………………. 20 2.7 Synthesis approach using double nucleophillic substitution.…………….. 20 2.8 Synthesis of bicyclic compound 73…………………………………….… 21 2.9 Retrosynthetic analysis using N-acyliminium ion cyclization

was the key step………………………………………………………..... 22 2.10 Synthesis of imide 76………………………………………………..…… 23 2.11 Reduction of imide 76 to alcohol 81………………………………...……. 23



x

List of Scheme

Scheme Page 2.12 Retrosynthetic analysis of epiquinamide...................................................... 24 2.13 Synthesis of bicyclic compound 74………………………………………... 25 2.14 Synthesis of aldehyde 90………………………………………………….. 26



xi

ABBREVIATIONS

DCC dicyclohexyl carbodiimide DIBALH diisobutyl aluminium hydride DMAP N,N-dimethylamino pyridine DMSO dimetylsulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride IR infrared LAH lithiun aluminium chloride NMR nuclear magnetic resonance spectroscopy rt room temperature TBAF tetrabutyl ammonium fluoride TBDPSCl tert-butyl diphenyl chlorosilane THF tetrahydrofuran TLC thin layer chromatography UV ultraviolet



1

CHAPTER 1

GENERAL INTRODUCTION

Alkaloids are a group of natural products that contain nitrogen atom in the molecule. Nitrogen atom may present in the forms of amine, amine oxide, amide and imide. Alkaloids have diverse and important physiological effects on humans and other animals. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals. The classification of alkaloids based on similarity of the carbon skeleton or biogenetic precursor give 4 types of alkaloids ; (1)True alkaloids, which contain nitrogen atom in a heterocycle and are originated from amino acid, for example atropine, nicotine and morphine. (2) Protoalkaloids, which also are biosynthesized from amino acid but contain nitrogen that is not in a ring, such as mescaline, adrenaline and ephydrine. (3) Polyalkamine alkaloids which are protoalkaloids that contain multiple nitrogen atoms such as derivatives of putrescine, spermidine and spermine. (4) Pseudoalkaloids which are alkaloid-like compounds that do not originate from amino acid such as caffeine, theobromine, theophylline, coniine and coniceine. The structures of these alkaloids are shown in Figure 1.1. Peptide and proteins containing nitrogen atom and are originated from amino acid. However these primary metabolites are not classified as alkaloids.

Furthermore, the classification of alkaloid based on the fundamental ring structure can divide them roughly into two main groups, namely non-heterocyclic (protoalkaloids) and heterocyclic alkaloids. The heterocyclic alkaloids can be subdivided into many classes according to the structure of the heterocycles, such as pyrrole-pyrrolidine, pyrrolizidine, pyridine and piperidine, tropane, quinolone, isoquinoline, tetrahydroisoquinoline, indole, and quinolizidine alkaloids. Structure of examples of these alkaloids are shown in Figure 1.2.



2

O

O

OHNH3C

Atropine

N

NCH3

H

Nicotine

HO

O

HHO

HN CH3

Morphine

O

OO

NH2

Mescaline

HO

HO

OH HN

CH3

Adrenaline

OH

HN

Ephedrine H2N NH2

Putrescine

H2N NH

HN NH2

Spermine

H2NHN NH2

Spermidine

N

N N

NO

O

Caffeine

HN

N N

NO

O

Theobromine

N

N N

HN

O

O

Thephylline

NH

CH3

Coniine

N

Coniceine

Figure 1.1 Structure of selected alkaloids.

3

N

O

Hygrine N

HOO

OCH2

HO CH3

O

Seneciphylline

N

NH

Nicotine

NH

piperidine

NH

O

NO

ricinine

O

O

OHN

HyoscyamineN

O

OH

N

Quinine

N

O

OO

O

Papavarine

NH

N

H HOH

OO

Yohimbine

NAcO

N

H

Aspidospermine

NH

tetrahydroiqoquinoline

(a tropane)

Figure 1.2 Structures of heterocyclic alkaloids of various structural types.

Quinolizidine alkaloids (norlupinane, octahydro-2H-quinolizine), have been studied in a number of laboratories during the last 100 years[1]. They represent about 2% of the 7000 known alkaloids from plants. Quinolizidine can be divided into more than 6 structural groups; 1. Lupinine and its esters. 2. The tetracylic quinolizidine, such as spateine and lupanine which can be modified by additional keto groups and up to two hydroxyl groups. The hydroxylated lupinines form esters with aliphatic and aromatic acids. 3. The α-pyridones [e.g. anagyrine]. 4. The tricyclic quinolizidine alkaloids with an allylic side chain instead of the fourth ring, such as tetrahydrorhombifoline.5. Matrine alkaloids. 6. Other types.

4

Figure 1.3 Structural type of quinolizidine alkaloids.

5

EPIQUINAMIDE: ISOLATION AND STRUCTURE ELUCIDATION

In 2003, Daly[2] and co-workers reported the isolation, structure elucidation, and pharmacology of epiquinamide. The alkaloid fraction of the methanolic skin extract from 187 frogs of the species Epidobates tricolor collected in 1987, containing ~1 mg/mL total alkaloids. Epiquinamide had a molecular formation of C11H20N2O. Daly and co-workers analyzed epiquinamide by HPLC-MS which showed an alkaloid 196, giving a protonated molecular ion at m/z 197 and affording a fragment at m/z 138 (M=H-59), consistent with a loss of acetamide by McLafferty rearrengment. Based on prior chiral GC analysis of synthetic and natural samples, the absolute structure of this alkaloids was established as (1S,9aS)-1-acetamidoquinolizidine. Since then, several group have undertaken synthetic efforts to produce this compound, which appeared initially to be a novel, β2-selective nicotinic acetylcholine receptor agonist. Synthetic epiquinamide is inactive at nicotinic receptors, in accord with recently published reports[3]. Daly and co-workers have determined that the activity initially reported is due to cross-contamination from co-occurring epibatidine in the isolated material.

N

ClHN

Epibatidine

N

HNHAc

Epiquinamide

Figure 1.4 Ecuadorain frog, Epidobates tricolor and structure of Epibatidine and Epiquinamide.

6

PREVIOUS SYNTHESES OF EPIQUINAMIDE

Since Daly and co-worker reported the isolation and structure elucidation of epiquinamide in 2003, there have been 5 reported synthetic studies toward this compound. The first synthesis of epiquinamide was reported in 2005 by Blaauw[4] and co-workers. Their retrosynthetic analysis is shown in scheme 1.1. Epiquinamide could be synthesized from N-acylhydroxypipecolic acid derivative 2. This key intermediate provided the bicyclic skeleton after a ring-closing metathesis. Amide 2 could be derived from methoxypipercolic acid derivative 3 via a diastereoselective allylation. N,O-acetal 3 could be synthesized from cyclization of protected L-allysine ethylene acetal 4 followed by a diastereoselective epoxidation/ring-opening strategy applied on the obtained cyclic enamide. In turn, L-allysine ethylene acetal can be readily obtained in enantiomerically pure form by biocatalytic resolution of the corresponding acid amide.

NH

AcHN

(+)-epiquinamide

N

HO

CO2Me

OR

2

NR

HO

CO2MeMeO

3

O

O

H2N CO2H

4

Scheme 1.1 Blaauw ’s retrosynthetic analysis of epiquinamide.

Blaauw ‘s synthesis of epiquinamide had bicyclic core 7 as an advanced intermediate. The reaction sequence to Cbz-protected pipecolic acid derivative 3a proceeds in an excellent yield of 94% over four steps, with a diastereoselectivity of 96:4 in favour of the desired (2S,5R)-isomer 2a (Scheme 1.2).

7

O

O

H2N COOH

NCbz

CO2Me

HO

MeO

4 3a

(2S,5R):(2S,5S) = 96:4

TMS

BF3OEt2, CH2Cl2-30oC rt, 95%

NCbz

CO2Me

HO

5de = >99%

1) HBr, AcOH, 0oC2) K2CO3 MeOH 85%

NH

CO2Me

HO

6

Cl

O

Et3N, CH2Cl265oC

N CO2Me

HO

2a

O

1) Grubbs 2nd cat2) H2, Pd/C, MeOH, rt

N

O

COOMeH

HO

7

Scheme 1.2 Blaauw ’s synthesis of the bicyclic core of epiquinamide.

Treatment of N,O-acetal 3a with BF3OEt2 in the presence of allyltrimethylsilane gave 2-allyl pipercolic acid derivative 5. Removal of the Cbz moiety under acidic conditions gave amine 6. Amine 6 was treated with acryloyl chloride to give diene 2a. Treatment of 2a with a catalytic amount of the Grubbs second generation ruthenium catalyst, followed by immediate hydrogenation of the double bond yielded the bicyclic 7. The synthesis was completed as depicted in Scheme 1.3. Mesylation of the alcohol, followed by treatment with sodium azide, resulted in the formation of azide 10. After saponification of methyl ester, a decarboxylation was performed to afford azido quinolizidinone 11. Redution by LAH completed Blaauw ’s synthesis of (+)-epiquinamide.

8

N

O

COOMeH

HO

7

1) MsCl, Et3NCH2Cl2, 0oC rt

2) NaN3, DMF, 100 oC79%

N

O

COOMeH

N3

101) NaOH, THF,

H2O, rt2) (i) iBuOC(O)Cl, NMM

THF, -15 oC(ii)

N SOH

Et3N, THF, -15 oC(iii) tBuSH, hv , THF, rt

N

O

H

N3

11

1) LAH, THF, rt 60oC

2) Ac2O, NaOH, dioxaneH2O, rt, 84%

NH

AcHN

1

Scheme 1.3 Blaauw ’s completion of the synthesis of epiquinamide.

Kanakubo[5] and co-workers reported the synthesis of (±)-epiquinamide with the key intermediate being the quinolizidine based ester 14. Methyl N-Boc homopipecolate 12 underwent a diastereoselective Michael reaction with diethyl methylenemalonate to provide diethyl ester 13 in 71% yield. N-Boc deprotection, lactamisation and decarboxylation gave the key ester intermediate 14 as a single diastereomer in 57% yield from 13. Hydrolysis of ester under acidic condition gave acid 15 which was subjected to Curtius rearrangement. Trapping the intermediate isocyanate with 9-fluorenylmethanol produced the product 16. Deprotection of Fmoc under standard conditions gave amine 17. Lactam reduction of aimde 17 was carried out using LAH and the crude product was acetylated to achieve racemic epiquinamide (Scheme 1.4).

9

N

HCO2Me

O14

1. (PhO)2P(O)N3 PhMe, 80oC2. 9-FMN

HNHFMoc

O

piperidine, DMF77%N

HNH2

O

1. LAH2. Ac2O dioxane 70%

N

HNHAc

NBoc

CO2Me CO2Et

CO2EtLHMDS, THF,-78oC

71%

NBoc

CO2MeH

CO2EtCO2Et

1. TFA2. NaCl, DMSO, H2O, heat, 57% over 2 steps

AcOH, HCl90oC

N

HCO2H

O

12 13

1516

17

(+)-epiquinamide

Scheme 1.4 Kanakubo ’s synthesis of (±)-epiquinamide

In 2006, Gerwick[6] and co-workers reported the practical total synthesis of epiquinamide enantiomers. Their retrosynthetic analysis is shown in scheme 1.5. Epiquinamide could be synthesized from diene 18 via ring closing metathesis. Diene 18 could be derived from mesylate 19 and mesylate 19 could be synthesized from ornithine derivative 20.

10

NH

NH

O

NHNHC��

OMs

NHBoc

NHC��

OBocHN

NHC��

O

epiquinamide 18

1920

Scheme 1.5 Gerwick ’s retrosynthetic analysis of epiquinamide.

The synthesis began with a commercially available ornithine derivative 20, which was converted to the Weinreb amide 21 using a common coupling condition. Upon treatment with allyl magnesium bromide ketone 22 was obtained. Reduction of ketone 22 yielded alcohol 23. Mesylation of the amino alcohol 23 produced mesylate 19 (Scheme 1.6).

11

OBocHN

NHC��

OMeO(Me)NH HCl

EDC�, Et3N

DMAP, CH2Cl293%

OBocHN

NHC��

NO

M�BrEt2O, -78oC

8�%

OBocHN

NHC��

LiAl(OtBu)3HEtOH, -78oC

�h, 93%HOBocHN

NHC��

MsCl, Et3NDMAP, CH2Cl2

97%

OMs

NHBoc

NHC��

20 21

2223

19

Scheme 1.6 Synthsis of mesylate 19.

Removal of the Boc group in TFA/CH2Cl2 followed by intramolecular SN2 cyclization by N-alkylation in acetonitrile yielded the diene 18. The synthesis of the epiquinamide skeleton was concluded by ring closing metathesis reaction on diene 18 using Grubbs’ second generation catalyst. Deprotection, alkene reduction, and acetylation were accomplished in one-pot by hydrogenation of 25 in ethanol with acetic anhydride to give epiquinamide (Scheme 1.7).

12

OMs

NHBoc

NHC��

TFA, CH2Cl2,0oC to rt, 30 minthen �2CO3(aq)

OMs

NH2

NHC��

�2CO3, MeCN�then more �2CO3,

Br73% over 2 steps

N

NHC��

H

�ru��s ��CH2Cl2, re�lux, 5h

83%

N

NHC��H

H2, Pd�C, Ac2OEtOH, 2d

�3%N

H HN

O

19 24 18

25

Scheme 1.7 Gerwick ’s synthesis of epiquinamide.

N

HNHAc

Epiquinamide (1)

N

HOH

O

N

O

HOTBS

HN

O

HO

O

BnN

O

OO H

OO

NHBn

HD-Mannitol

26 27 28

2930

Scheme 1.8 Ghosh’s retrosynthetic analysis of epiquinamide.

Ghosh[7] and co-worker reported the total synthesis of (+)-epiquinamide from D-mannitol in 2009. Their retrosynthetic analysis is shown in scheme 1.8. Epiquinamide could be obtained from hydroxy quinolizidinone 26, which in turn could be obtained from diene 27

13

via ring-closing metathesis. Diene 27 could be obtained by means of N-allylation of lactam 28, which could be synthesized though ring-closing metathesis of diene 29 which in turn, was obtained from known compound 30.

BnN

O

OO HO

O

NHBn

H

2930

D-mannitol

3-�utenoic acid,iso�ut�lcholro�ormateNMM, THF, 0oC to rt

8 h, 87%

�ru��s� 1st�eneration catal�st

BnN

O

HO

O

31

H2, Pd-C, MeOHrt, 0.5 h, 90%

BnN

O

HO

O

32

Li, liq. NH3THF, -78oC

1 h, ��%HN

O

HO

O

28

NaH, all�l �romide,DMF, 0oC to rt, 2 h

83%

N

O

HO

O

33

1. CSA, MeOH, rt, � h 77%2. TBSOT�, 2,�-lutidine, CH2Cl2, 0oC, 0.5 h, 9�%3. HF-P�, THF, rt, 1� h, 8�%

N

O

HTBSO

HO

34

1. DMP, CH2Cl2, 0oC to rt, 1.5 h2. Ph3P�CHCOOEt, CH2Cl2, rt, 1 h 8�%

N

O

HTBSO

35�ru��s� 1st�enerationcatal�st, CH2Cl2, 71%

N

O

HTBSO

36

1. Pd-C, H2, MeOH, 90%2. TBAF, THF, rt, 7 h, 89%

N

O

HOH

26

1. Ms-Cl, Et3N, CH2Cl2 0.5 h2. NaN3, DMF, 100oC, 50% over 2 stepsN

O

HN3

37

1. LAH, THF, re�lux, 2� h2. Ac2O, 1N NaOH, dioxane, 2 h, 79% over 2 steps

N

HNHAc

(+)-epiquinamide

EtOOC

Scheme 1.9 Ghosh’s synthesis of epiquinamide.

14

The synthesis of diene compound 29 (Scheme 1.9) commenced from acetonide 30, which was prepared from D-mannitol according to the reported procedure[8, 9, 10]. N-acylation with 3-butanoic acid using isobutylchloroformate and NMM in THF afforded compound 29 which underwent ring-closing metathesis with Grubbs’ 1st generation catalyst in CH2Cl2 at 50 °C for 6 h and gave six-membered lactam 31. Compound 31 was hydrogenated under atmospheric pressure using hydrogen balloons and Pd-C as a catalyst in methanol to afford lactam 32. The N-benzyl group was removed under Li/liq. NH3 condition to give compound 28. N-allylation of compound 28 with NaH and allyl-bromide in DMF afforded N-allyl lactam 33, which was converted to diene 35 in 5 steps. Acetonide deprotection followed by routine protecting-group manipulations afforded primary alcohol 34. Oxidation of the primary alcohol with DMP followed by Wittig olefination with stable ylide Ph3P=CHCOOEt furnished diene 35. Accordingly, compound 35 was treated with Grubbs’ 1st generation catalyst to give bicyclic 36 in 71% yield. Reduction of the double bond followed by TBS deprotection afforded secondary alcohol 26. Compound 26 was converted to azide 37 in two steps; mesylation followed by mesyl displacement with NaN3. Finally azide 37 was converted to epiquinamide according to the reported procedures[4, 11, 12].

Chandrasekhar[13] and co-worker reported the stereoflexible total synthesis of (-)-epiquinamide in 2009. Their retrosynthetic analysis shown in scheme 1.10. Epiquinamide could be obtained from alcohol 38. Alcohol 38 could be synthesized from lactone 39, which in turn could be obtained from the key steps including the propagyl alcohol rearrangement to all trans diene ester 40, Sharpless asymmetric dihydroxylation and one-pot reduction-lactonization.

N

NHAc

(-)-epiquinamide

N

OH

O

O

O

N3

TBSO

TBSOCO2Et

HO OH�

38 39

4041

Scheme 1.10 Chandrasekhar’s retrosynthetic analysis of (-)-epiquinamide.

15

The synthesis was initiated with the commercially available 1,6-hexane-diol 41. Selective monosilylation of diol 41 followed by oxidation of alcohol using BAIB and TEMPO afforded aldehyde 42. The lithiated ethyl propiolate was added to aldehyde 42 to yield the hydroxyl ethyl propiolate 43. Hydroxyl ethyl propiolate 43 was stirred in benzene in the presence of PPh3 to yield the (E,E)-diene ester 40. The diene ester 40 was subjected to the enantio- and regio-selective Sharpless asymmetric dihydroxylation using Admix-α to yield the diol 44 (Scheme 1.11).

HO OH�

1. TBSCl, �mida�ole, CH2Cl2 30 min, 0oC, 75%2. BA�B, TEMPO, CH2Cl2 0oC to rt, 2h, 92%

TBSO H�

O

CO2Et, LiHMDSTHF, -78oC, 30 min

77%

TBSOOH

CO2Et

PPh3, �en�ene, rt,3h, 8�%

TBSOCO2Et

CH3SO2NH2,tBuOH�H2O (1�1)ADmix 0oC, �8h, 80oC

TBSOCO2Et

OH

OH

41 42

4340

44

Scheme 1.11 Chandrasekhar’s synthetic analysis of the diol 44.

The diol 44 was subjected to hydrogenation , followed by heating to reflux in THF in the presence of K2CO3 to give butyrolactone 45. The secondary hydroxyl group was transformed to the azido group to realize azide 39, the silyl ether group in 39 was transformed to mesylate 47 via alcohol 46. The mesylate 47 was subjected to one-pot reduction-double cyclization involving azide reduction to amine which underwent intramolecular cyclization displacing mesylate. Another facile lactamization opened up the butyrolactone ring to furnish

16

the hydroxyl quinolizidinone 38. The acetamino group was installed as hydroxy quinolizidinone 38 was converted to (-)-epiquinamide via mesylation, azide substitution and reduction (Scheme 1.12).

TBSOCO2Et

44

OH

OH

Pd-C�H2, EtOAc, rt, �hthen �2CO3, THF re�lux

10h, 75% OO

TBSO

HO

45

1. TsCl, Et3N, DMAP CH2Cl2, 0oC to rt, 12h2. NaN3, DMF, �8oC, �h 80%

OO

TBSO

N3

39

p-TSA, MeOHrt, 30 min, 81%

OO

HO

N3

46

MsCl, Et3N, CH2Cl2-10oC, 15 min

OO

MsO

N3

47

Pd-C�H2, EtOH, 10hthen �2CO3, EtOH

re�lux, �h, 55%N

O

OH

1. MsCl, Et3N, CH2Cl2, -10oC, 15 min2. NaN3, DMF, �50C, 3�h3. LAH, THF, re�lux then Ac2O NaOH (1N)

N

NHAc

(-)-epiquinamide

38

Scheme 1.12 Chandrasekhar’s synthetic analysis of (-)-epiquinamide.

17

CHAPTER 2

TOTAL SYNTHESIS OF EPIQUINAMIDE

First route toward epiquinamide uses tandem nucleophilic substitution/lactol formation and ring closing metathesis as the key steps. We envisioned that epiquinamide could be synthesized from bicyclic 48. The quinolizidine ring of epiquinamide could be synthesized from ring closing metathesis of diene 49 followed by lactol reduction. Lactol 49 would be prepared from 3-butenylamine hydrochloride and enone 50. Enone 50 would be obtained in 4 steps from diol 51 via standard chemistry and diol 51 would be obtained from (L)-glutamic acid in 2 steps (Scheme 2.1).

N

NHAc

epiquinamide 1

N

NBn2

48 49

O O�

NBn2

OH

NBn2

OH

51

HO

O

OH

O

NH2

(L)-�lutamic acid 52

N

NBn2OH

NH2

50

Scheme 2.1 Retrosynthetic analysis of epiquinamide. Synthetic study of epiquinamide started from benzylation of (L)-glutamic acid (52) with benzyl chloride in the solution of MeOH:H2O (1:1) to give a mixture of benzyl N,N-dibenzyl glutamate 53 in moderate yield. Reduction of benzyl ester 53 by litium aluminum hydride gave diol 51 in quantitative yield. The diol 51 was treated with tert-butyl diphenylchlorosilane to give a mixture of silyl ethers; disilyl ether 55, monosilyl 54 with silyl protection on the more hindered side, monosilyl 56 with silyl protection on the less hindered side. Silyl ether 54 underwent oxidation of 1°-alcohol with Swern oxidation to provide aldehyde 57 (Scheme 2.2).

18

HO

O

OH

O

NH2


BnCl, NaOH, �2CO3MeOH�H2O (1�1)

BnO

O

OBn

O

NBn2

53

LAH, THFOH OH

NBn2

51

TBDPSCl, Et3N,DMAP

OH OTBDPS

NBn2

54

OTBDPS OTBDPS

NBn2

55

OTBDPS OH

NBn2

56

S�ern OxidationO OTBDPS

NBn2

57

H

Scheme 2.2 Synthesis of aldehyde 57.

In an attempt to synthesize diene 49, we carried out three reactions to prepare alcohol 58, 59 and 60 which in turn would be converted to ketone precursors of diene 49. Vinylation of aldehyde 57 with vinyl magnesium bromide was unsuccessful. However, treatment of aldehyde 57 with allyl magnesium bromide and 1-propynylmagnesium bromide afforded allyl alcohol 59 and alkynl alcohol 60, respectively (Scheme 2.3).

O OTBDPS

NBn2

57

H

M�Br

M�Br

M�Br

OH OTBDPS

NBn2

58

OH OTBDPS

NBn2

59

OH OTBDPS

NBn2

607�%

21%

Scheme 2.3 Grignard reaction of aldehyde 57 with various Grignard reagents. The absolute configuration of the newly generated stereocenter was tentatively assigned as R according to Felkin-Ahn’s model. However, the configuration of the stereocenter was inconsequential because the next step was oxidation of this hydroxyl group to the corresponding ketone. (Scheme 2.4).

19

OH OTBDPS

NBn2

59

S�ern Oxidation

NBn2

O OTBDPS61

NBn2

O OTBDPS62

Scheme 2.4 Oxidation of homoallyl alcohol 59.

We found that Swern oxidation of allyl alcohol 59 proceed smoothly to give alkene-ketone 61 and unexpected isomerized product 62. They were separable by flash column chromatography. The separated enone 62 which was a proper precursor for conversion to diene 49, reacted with tetrabutylammonium fluoride in THF to achieve alcohol 63 which was treated with Tf2O to provide triflate 64. The triflate 64 was treated with 3-butenylamine hydrochloride in the presence of K2CO3 in DMF in an attempt to affect tandem nucleophillic substitution and lactol formation. However this attempt was unsuccessful (Scheme 2.5).

O OTBDPS

NBn2

62

TBAFO OH

NBn2

63

T�2OO OT�

NBn2

64

NH2.HCl �2CO3, DMF

N

OH NBn2

49

�2%

Scheme 2.5 Attemp to synthesized diene 49.

Because of the unsatisfied result, we modified our strategy toward bicyclic compound 48. We hypothesized that the bicyclic system precursor diene 49 would be obtained from double nucleophilic displacement of bis-trifflate 64. Accordingly the synthesis of bicyclic compound 48 started from reduction of propagyl alcohol 60 with Red-Al or H2/Pd on barium sulfate to yield E-alkene 65 or Z-alkene 66, respectively (Scheme 2.6).

20

H3C

OH

NBn2

OTBDPS

60

�ed-Al

Pd� BaSO�

OH

H3C

OTBDPS

NBn2

65

CH3 OH OTBDPS

NBn2

66H2 (�.)

Scheme 2.6 Reduction of propagyl alcohol 60. Deprotection of silyl group of alkene 66 with tetrabutylammonium fluoride in dry THF at 0°C provided diol 67. We expected that treatment of diol 67 with Tf2O would provide ditriflate 68, which would lead to piperidine-diene 69 upon reaction with 3-butenylamine hydrochloride via double nucleophillic displacement with inversion of configuration at the secondary triflate for the desired configuration. Subsequent ring closing metathesis should provide the quinolizidine system 48. However, N,N-dibenzyl pyrrolidine ion 70 was obtained instead via intramolecular substitution of the primary triflate with dibenzylamino N atom. (Scheme 2.7).

CH3 OH OTBDPS

NBn2

66

TBAFCH3 OH OH

NBn2

67

T�2O CH3 OT� OT�

NBn2

68

NH2.HCl

N

NBn269

�ru��s� cat.

N

NBn2

48

T�2O

NBn Bn O�

70

H

H

�2%

Scheme 2.7 Synthesis approach using double nucleophillic substitution.

Discouraged by several unsuccessful attempts, and inspired by elegant synthesis of aspidophytine by E.J. Corey[14] using cascade iminium ion cyclization, we turned to an alternative approach using similar strategy. Diol 51 was converted to dialdehyde 71 by Swern oxidation. We expected that treatment of this dialdehyde with 3-butenylamine hydrochloride would result in first enamine formation of the first carbonyl then lactol formation of the

21

enamine with the second aldehyde and finally N-allyliminium ion cyclization in presence of a Lewis acid. However the desired product was not obtained from this reaction (Scheme 2.8).

OH OH

NBn2

51

S�ern OxidationO O

NBn2

71

H H

NH2 HCl

N

NBn2

HO

72

BF3OEt2N

NBn2

73

NaBH�

Scheme 2.8 Synthesis of bicyclic compound 73.

In our previous studies of quinolizidinone alkaloids, we employed N-acyliminium ion cyclization in the synthesis of 2-amino quinolizidinone 79. The in situ N-acyliminium ion was obtained from selective reduction of the imide 76 at the less hindered carbonyl. If a selective reduction at the more hindered carbonyl can be achieved to result in hydroxyl lactam 75, treatment of this intermediate with a Lewis acid might give quinolizidinone 74. Then epiquinamide could be derived from the bicyclic compound 74 by lactam reduction and tandem hydrogenation/N-acetylation.

22

N

NHAc

epiquinamide

N

O

NBn2

NHO O

Bn2N7475

NH

O O

OBnNBn2

77

HO

O

NH2

O

OH


NO O

Bn2N

76

NO OH

Bn2N

78

NO

Bn2N79

Scheme 2.9 Retrosynthetic analysis using N-acyliminium ion cyclization as the key step.

Our synthetic study of epiquinamide using N-acyliminium ion cyclization as the key step has imide 76 as the crucial intermediate and its synthesis was accomplished in the same manner as in our previous studies of other quinolizidine alkaloids. This started from benzylation of (L)-glutamic acid with benzyl cholride, NaOH, K2CO3 in refluxing MeOH/H2O (1:1) to yield benzyl ester 80. Amide formation of benzyl ester 80 with 3-butenylamine hydrochloride in the presence of EDC and DMAP gave amide product 77 in 70% yield. In attempts to prepare imide 76, LDA, NaBH4, tBuOK and LAH were used. However, LAH was the best choice of base for providing imide 76 from cyclization of amide 77. In this step hydroxylactam 78 was also obtained (Scheme 2.10).

23

HO

O

OH

O

NBn2


BnCl, NaOH, �2CO3MeOH�H2O (1�1)

HO

O

OBn

O

NBn2

80

NH2DMAP, EDC, 70%

NH

O

OBn

O

NBn2

77

LAH, THF0oCN OO

Bn2N

76 (35%)

N OHO

Bn2N

78 (33%)

HCl

53%

Scheme 2.10 Synthesis of imide 76.

Our previous results of imide reduction using stoichiometric reducing agents such as LAH and DIBALH gave exclusively hydroxylactam with selective reduction at the less hindered carbonyl. We suspected that usage of large excess of reducing agent might at least give non-selective reduction and the mixture of hydroxylactam 75 and 78 could be obtained and separated. However, attempts to synthesize hydroxylactam 78 from imide 76 using excess NaBH4, DIBALH and LAH were unsuccessful. The result showed that all reducing agents gave undesired alcohol 81 (Scheme 2.11).

N OO

Bn2N

76

LAH

NaBH�

D�BALH

NHO

Bn2N

81

OH

Scheme 2.11 Reduction of imide 76 to alcohol 81.

24

With many failed approaches, our eventual strategy also relies on N-acyliminium ion cyclization. However due to the failure of synthesizing hydroxylactam 75 via selective imide reduction, an alternative approach toward that key intermediate has to be devised.

N

NHAc

Epiquinamide (1)

N

NBn2

O

74

N

NBn2

O

82

N

NBn2

O

75

HOTBDPSO O

NBn2

84

OH

HO

O

OH

O

NH2


H

NH

NBn2

O

83

HO

NH2 HCl

Scheme 2.12 Retrosynthetic analysis of epiquinmide.

In our revised and most current retrosynthetic analysis, we envisioned the hydroxylactam 75 to be obtained from oxidation of primary alcohol 83, which in turn would be prepared carboxylic acid 84 and 3-butenylamine hydrochloride. The carboxylic acid 84 could be prepared from (L)-glutamic acid 52 in 4 steps via benzylation, reduction, TBDPS-protection and oxidation respectively. In this regard, the carbonyl group adjacent to the stereocenter in (L)-glutamic acid would be converted to a protected alcohol in compound 84 (Scheme 2.12).

25

HO

O

OH

O

NH2

(L)-glutamic acid 52

BnCl, NaOH,�2CO3MeOH�H2O (1�1)

HO

O

OBn

O

NBn2

80LAH, THF0 oC, 98%

OH OH

NBn2

51

NaH, THFTBDPSCl 39%

56

�ones rea�ent �3%

TBDPSO O

NBn284

OH

TBDPSO OH

NBn2

NH2 HCl

DMAP, EDCCH2Cl2, 70%

TBDPSO O

NBn285

NH

TBAF, 99%

OH O

NBn2 83

NHS�ern oxidation

O O

NBn286

NH

H

53%

N

O

NBn2

OHN

O

NBn2H

TMSOT�CH2Cl2

quantitative

75%75 74

sin�le diastereomer

Scheme 2.13 Synthesis of bicyclic lactam 74.

Diol 51, synthesized as previously described, was used as the starting point in this approach. Treatment of the diol with TBDPSCl in the presence of NaH in THF afforded monosilyl ether 56 with silyl protection selectively on the more hindered side in 39% yield probably due to the chelation control of Na-metal and nitrogen atom. Oxidation of alcohol 56 with Jones reagent produced carboxylic acid acid 84 in 43% yield. Coupling of acid 84 and 3-butenylamine hydrochloride in the presence of DMAP and EDC proceeded smoothly to give amide 85 in 70% yield. Deprotection of the silyl ether with TBAF gave amide alcohol 83. Swern oxidation of the hydroxyl group then afforded aldehyde 86. The aldehyde was in an equilibrium with hydroxylactam 75 and its reaction with TMSOTf resulted in in situ

26

generation of N-acyliminium ion. Cyclization by this intermediate gave bicyclic lactam 74 as a single diastereomer along with trace amount of its olefinic regioisomer. The protected amino quinolizidinone framework of this compound is equipped for the completion of the total synthesis of epiquiamide with further steps of functional group conversions (Scheme 2.13).

HO

O O

OBnNBn2

87

NH

O O

OBnNBn2

88

NH2 HCl

(Boc)2O, Et3N

N

O

NBn2

O

OBnBoc

D�BALHN

O

NBn2

O

HBoc

8990

DMAP, CH2Cl253%

(over 2 steps)

CH2Cl2(quantitative)

DMAP, CH2Cl2

Scheme 2.14 Synthesis of aldehyde 90.

Furthermore, we attemped to synthesized Epiquinamide using N-acyl iminium ion cyclization as the key reaction and benzyl ester 87 as the starting material. This started from amide formation of benzyl ester 87 and 3-butenylamine hydrochloride to yield amide 88. Treatment of the amide 88 with (Boc)2O in the presence of Et3N and DMAP in CH2Cl2 gave protected amide 89. Reduction of benzyl with DIBALH afforded aldehyde 90 in quatitative yield (Scheme 2.14).

We expected that the protected aldehyde 90 is converted for the completion of the total synthesis of epiquiamide with further steps of functional group conversions.

27

CHAPTER 3

GENERAL CONCLUSION

Aminodehydroquinolizidinone intermediate 74 for total synthesis of epiquinamide was synthesized from L-glutamic acid in 8 steps and 3.5% overall yield. The key features of the synthesis were differentiation of the L-glutamic acid 2 carboxyl groups via reduction/protection/oxidation, and highly diastereoselective N-acyliminium ion cyclization. This strategy was reached after other approaches had failed. In terms of number of synthetic steps, our approach compares relatively well with other reported syntheses. However the overall yield is very low due to a few problematic steps. The efficiency of the synthesis was diminished by steps with fluctuation in oxidation states of the intermediates and protection/deprotection sequence. Oxidation of primary alcohol to carboxylic acid using Jones reagent in the presence of dibenzylamino group gave a very low yield due to complication from Cope elimination.

28

CHAPTER 4

EXPERIMENTAL PROCEDURES

General Methods. Starting materials and reagents were obtained from commercial sources and were used without purification. Solvent were dried by distillation from the appropriate drying reagent immediately prior to use. Moisture and air-sensitive compounds were used under an argon atmosphere with oven-dried glassware. Analytical thin-layer chromatography (TLC) was conducted using Fluka pre-coated TLC plates (0.2 mm layer thickness of silica gel 60 F-254). Compounds were visualized by ultraviolet light and/or by heating the plate after dipping in a 1% solution of vanillin in 0.1 M sulfuric acid in ethanol. Flash chromatography was carried out using silica gel (0.06-0.23 mm particle size). Optical rotations were measured with a JASCO P-1010 polarimeter. Infrared (IR) spectra were recorded on Perkin-Elmer spectrum GX FT-IR spectrometer. Major bands (νmax) were recorded in wave number (cm-1). Nuclear magnetic resonance (NMR) spectra were obtained in CDCl3, unless otherwise noted, on a 300 MHz Bruker spectrometer. Chemical shifts are in δ (ppm) with tetramethylsilane as an internal standard. Coupling constants are reported in hertz (Hz).

29

SYNTHESIS OF EPIQUINAMIDE

HO

O

OBn

O

NBn2

(S)-5-(benzyloxy)-2-(dibenzylamino)-5-oxopentanoic acid (39). (L)-glutamic acid (5 g, 0.03 mol) was dissolved in 100 mL of MeOH:H2O (1:1). To this solution was added benzyl chloride (15.64 mL, 0.13 mol), K2CO3 (10.56 g, 0.07 mol) and NaOH (3.06 g, 0.07 mol). The reaction was heated to reflux overnight. 1M HCl (50 mL) and H2O (50 mL) were added and then the mixture was extracted with CH2Cl2 (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude material as a yellow oil. The crude product was purified by column chromatography to give the monobenzoate product 39 as yellow oil (7.64 g, 53 %), 1H NMR (300 MHz, CDCl3) δ : 7.45-7.12 (m, 15H); 5.32 (d, 1H, J= 12.2 Hz); 5.08 (d, 1H, J= 12.2 Hz); 3.90 (d, 2H, J= 13.6 Hz); 3.48 (d, 2H, J= 13.6); 3.38 (t, 1H, J= 6.9 Hz); 2.37 (m, 2H); 13C NMR (75 MHz, CDCl3) δ : 178.9; 172.1; 138.9; 128.9; 128.7; 128.6 (2C); 128.4; 128.3; 127.1; 66.3; 59.8; 54.4; 30.7; 23.9; [α]D

25.4 -74.7° (c = 1.50, CHCl3); IR (film) 3066, 2959, 1950, 1700, 1600, 1476, 1450, 1370, 1217, 1160 cm-1. The corresponding dibenzyl ester 53 was also obtained as yellow oil (1.8 g, 12%)

BnO

O

OBn

O

NBn2

(S)-dibenzyl 2-(dibenzylamino)pentanedioate (53). 1H NMR (300 MHz, CDCl3) δ : 7.50-7.20 (m, 20H), 5.29 (d, 2H, J= 12.2 Hz); 5.15 (d, 2H, J= 12.2 Hz); 5.00 (d, 1H, J= 12.4 Hz); 4.95 (d, 1H, J= 12.4 Hz); 3.88 (d, 2H, J= 13.7 Hz); 3.50 (d, 2H, J= 13.8 Hz); 3.53-3.50 (m, 1H); 2.56-2.43 (m, 1H); 2.40-2.28 (m, 1H); 2.10-2.00 (m, 2H); [α]D

25.0 -65.63° (c = 16.84, CHCl3); IR (film) 3070, 2951, 1950, 1710, 1600, 1496, 1420, 1370, 1217, 1160 cm-1.

OH OH

NBn2

(S)-2-(dibenzylamino)pentane-1,5-diol (51).To a solution of benzyl glutamate mixture (10.41 g, 20.57 mol) in dry THF ( 100 mL) at 0 oC under argon atmosphere was added LAH (2.34 g, 61.72 mmol) and the mixture was stirred for 30 min. The reaction was quenched with sat. NaHCO3 (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated to give the diol 51 (3.44 g, 98%) as an orange oil. 1H NMR (300 MHz, CDCl3) δ : 7.34-7.22 (m, 10H); 3.88 (d, 2H, J=

30

13.2 Hz); 3.63 (t, 2H, J= 6.3 Hz); 3.42 (d, 2H, J= 13.2 Hz); 2.85-2.76 (m, 4H); 1.90-1.20 (m, 4H); 13C NMR (75 MHz, CDCl3) δ : 139.27; 129.35; 129.00; 128.80; 128.63; 128.46; 127.21; 62.44; 60.83; 58.73; 53.22; 30.08; 29.86; 26.87; 21.54; [α]D

25.0 +46.15° (c = 1.34, CHCl3); IR (film) 3373, 2937, 2865, 1712, 1655, 1602, 1494, 1454 cm-1.

OH O�B��

NBn2 (S)-5-((tert-butyldiphenylsilyl)oxy)-2-(dibenzylamino)pentan-1-ol (54). To a solution of diol 51 (0.1 g, 3.01 mmol) in dry CH2Cl2 (10 mL) under argon atmosphere was added N,N-dimethyl amino pyridine (0.001 g, 0.01 mmol), Et3N (0.06 mL, 0.45 mmol) and TBDPSCl (0.12 mL, 0.45 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with sat. NaHCO3 (20 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over anh. NaSO4 , filtered, and concentrated under reduced pressure. Purification by column chromatography (silica gel, 10:1 hexane : ethyl acetate) gave silyl alcohol 54 (7.64 g, 53%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.72-7.14 (m, 20H); 3.87 (d, 2H, J= 12 Hz); 3.60-3.51(m, 2H); 3.47 (d, 2H, J= 12 Hz); 3.42-3.36 (m, 2H); 2.77-2.69 (m, 1H); 1.89-1.80(m, 2H); 1.54-1.15(m, 2H); 1.09(S, 9H); 13C NMR(75 MHz, CDCl3) δ : 139.32; 135.97; 135.61; 135.33; 134.81; 133.98; 130.09; 129.67; 129.60; 129.39; 129.04; 128.84; 128.74; 128.64; 128.48; 128.19; 127.68; 127.46; 127.21; 126.72; 63.73; 63.21; 60.89; 58.90; 58.83; 58.67; 53.25; 30.18; 26.59; 21.15; 19.24; [α]D

25.0 +28.44° (c = 1.34, CHCl3); IR (film) 3422, 3069, 2931, 2892, 2857, 1602, 1588, 1494, 1472, 1455, 1427 cm-1.

O�B�� OH

NBn2 (S)-5-(tert-butyldiphenylsilyloxy)-4-(dibenzylamino)pentan-1-ol (56). To a striring solution of 60% NaH (0.15 g, 28.9 mmol) in dry THF under argon atmosphere was added diol 51 (2.15 g, 7.21 mmol) and tert-butydiphenylchlorosilane (7.39 mL, 28.9 mmol) and stirred for 3 hours. The reaction was quenched with sat. NaHCO3 (30 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated to give the crude product. Purification by column chromatography gave silyl ether 56 (1.5 g, 39 %) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.73-7.21 (m, 20H); 3.87(d, 2H, J= 13.62 Hz); 3.79-3.74 (dd, 2H, J= 5.06, 5.10 Hz); 3.54 (d, 2H, J= 13.62 Hz); 3.49-3.45 (t, 2H, 5.75 Hz); 2.82-2.79 (m, 1H); 1.14 (S, 9H); 13C NMR (75 MHz, CDCl3) δ: 140.43; 135.72; 135.68; 133.54; 133.44; 129.73; 129.69; 128.92; 128.13; 127.71; 126.76; 63.79; 62.91; 58.40; 30.13; 26.93; 24.97; 19.20; [α]D

25.0 -29.23° (c = 4.62, CHCl3); IR (film) 3422, 3028, 2931, 2857, 1602, 1588, 1494, 1455, 1389 cm-1.

31

H

O O�B��

NBn2 (S)-5-((tert-butyldiphenylsilyl)oxy)-2-(dibenzylamino)pentanal (57). To a solution of oxalyl chloride (0.8 mL, 9.14 mmol) in dry CH2Cl2 (65 mL) at -78 oC under argon atmosphere was added dropwise DMSO (1.30 mL, 18.30 mmol) after 30 min, the alcohol 54 (1.00 g, 3.05 mmol) in dry CH2Cl2(3 mL) was added slowly. The mixture was stirred at -78 C̊ for 1 h. Et3N (3.8 mL, 27.43 mmol) was added at -78 ̊C. The mixture was allowed to warm to room temperature over 45 min. The reaction was quenched with H2O (30 mL) and extracted with CH2Cl2 (3×70 mL). The combined organic layers were dried over anh. NaSO4 , filtered, and concentrated to give the aldehyde 57 (0.99 g, 99%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 9.68 (S,1H); 7.66-7.22 (m, 20H); 3.79-3.62 (dd, 4H, J= 13.8, 27.3 Hz); 3.62-3.60 (m, 2H); 3.13 (t, 1H, J= 3.6 Hz); 1.79-1.74 (m, 2H); 1.61-1.56 (m, 2H); 1.05 (S, 9H).

OH O�B��

NBn2 (5S)-8-((tert-butyldiphenylsilyl)oxy)-5-(dibenzylamino)oct-1-en-4-ol (59). To a solution of aldehyde 57 (0.70 g, 1.3 mmol) in dry THF (30 mL) was added allyl magnesium bromide (3.9 mL, 3.9 mmol) at -78 ̊C. The mixture was quenched with sat. NH4Cl (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated. Purification by column chromatography (Silica gel, 10:1 hexane:ethyl acetate) to give homoallyl alcohol 45 (0.23 g, 33%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.73-7.22 (m, 20H); 5.80-5.66 (m, 1H); 5.08-5.02 (m, 2H); 3.87-3.77 (m, 1H); 3.72-3.57 (m, 5H); 2.64-2.52 (m, 1H); 2.36-2.32 (m, 1H); 2.12-2.01 (m, 1H); 1.85-1.69 (m, 3H); 1.66-1.55 (m, 2H); 1.06 (s, 9H); [α]D

25.0 +1.70° (c = 1.42, CHCl3); IR (film) 3384, 3071, 2926, 2855, 1717, 1640, 1460, 1428.

OH O�B��

NBn2 (5S)-8-((tert-butyldiphenylsilyl)oxy)-5-(dibenzylamino)oct-2-yn-4-ol (60). To a solution of aldehyde 57 ( 0.32 g, 0.59 mmol) in dry THF (10 mL) was added 1-propynyl magnesium bromide ( 2.38 mL, 1.19 mmol) at 0 ̊C. The mixture was stirred at 0 ̊C under argon atmosphere for 30 min.The reaction was quenched with sat. NH4Cl (10 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anh. NaSO4 , filtered, and concentrated. Purification by column chromatography (silica gel, 10:1 hexane : ethyl acetate) to give propargylic alcohol 60 (0.25 g, 74%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.82-7.20 (m, 20H); 4.23 (s, 1H); 4.13(d, 2H, J= 13.2 Hz); 3.67 (m, 1H); 3.50 (d, 2H, J= 13.2 Hz); 2.80-2.74 (m, 1H); 2.10-1.87 (m, 1H); 1.75 (s, 3H); 1.70-1.75 (m, 2H), 1.56-1.40 (m, 1H); 1.10 (s, 9H); 13C NMR (75 MHz, CDCl3) δ: 139.37 (2C); 135.62 (2C); 133.99 (2C); 129.65; 129.24; 128.98; 128.47; 128.27; 127.67; 127.24; 126.98;82.20, 78.94; 63.80;

32

60.85; 60.67; 60.21; 54.90; 36.65; 29.83; 29.37, 28.48; 27.59; 26.93; 26.59; 24.70; 23.85; 23.36; 22.70; 21.45; 19.26; 14.12; 7.92; 3.64; ( [α]D

25.0 -1.66° (c = 2.1, CHCl3); IR (film) 3385, 2923, 2853, 1655, 1589, 1494, 1460, 1428.

O O�B��

NBn2 (S)-8-((tert-butyldiphenylsilyl)oxy)-5-(dibenzylamino)oct-1-en-4-one (61). To a solution of oxalyl chloride (0.06 mL, 0.77 mmol) in dry CH2Cl2 (5 mL) at -78 oC under argon atmosphere was added dropwise DMSO (0.1 mL, 1.54 mmol) after 30 min, alcohol 59 (0.15 g, 0.26 mmol) in dry CH2Cl2 (0.5 mL) was added slowly. The mixture was stirred at -78 oC for 1 h. Et3N (0.32 mL, 2.31 mmol) was added at -78 ̊C. The mixture was allowed to warmed to room temperature over 45 min. The reaction was quenched with H2O (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over anh. NaSO4 , filtered, and concentrated to give ketone 61 along with ketone 62 as a yellow oils. 61: 1H NMR (300 MHz, CDCl3) δ : 7.41-7.23 (m, 20H); 6.89-6.79 (m, 1H); 6.12 (d, 2H, J= 15.6 Hz); 3.81 (d, 2H, J= 13.5 Hz); 3.50 (d, 2H, J= 9 Hz); 3.47 (d, 1H, J= 3Hz); 2.80-2.68 (m, 1H); 2.49 (t, 2H, J= 7.5 Hz); 2.22-2.08 (m, 1H); 1.91 (d, 2H, J= 6.9 Hz); 1.62-1.48 (m, 2H).

O O�B��

NBn2 (S,E)-8-((tert-butyldiphenylsilyl)oxy)-5-(dibenzylamino)oct-2-en-4-one (62). 1H NMR (300 MHz, CDCl3) δ : 7.67-7.28 (m, 20H), 6.21-6.10 (m, 1H), 5.00-4.87 (m, 1H), 3.88-3.12 (m, 4H), 2.9 (m, 4H), 2.57-2.09 (m, 4H), 1.04 (s, 9H).

O OH

NBn2 (S,E)-5-(dibenzylamino)-8-hydroxyoct-2-en-4-one (63). To a solution of silyl ether 62 (0.09 g, 0.16 mmol) in dry THF (5 mL) was added TBAF (0.14 ml, 0.05 mL) at 0 ̊C. The mixture was stirred at room temperature under argon atmosphere for 1 h. The reaction was quenched with sat. NaHCO3 (3 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anh. NaSO4 , filtered, and concentrated. Purification by column chromatography (silica gel, 4:1 hexane : ethyl acetate) to give the diol (0.04 g, 40% ) as a yellow oil.

33

O O��

NBn2 (S,E)-4-(dibenzylamino)-5-oxooct-6-en-1-yl trifluoromethanesulfonate (64). To a solution of alcohol 63 (0.014 g, 0.07 mmol), 2,6-lutidine (0.01 mL, 0.07 mmol) in dry CH2Cl2 (3 mL) at -78 ̊C under argon atmosphere was added Tf2O (0.07 mL, 0.04 mmol) and stirred for 1 h. The reaction was quenched with sat.NaHCO3 (5 mL) and extracted with EtOAc (3×10 mL). The combined the organic layers were dried over anh. NaSO4 , filtered, and concentrated to give triflate (0.005 g, 40%).

H��

OH O�B��

NBn2 (5S,E)-8-((tert-butyldiphenylsilyl)oxy)-5-(dibenzylamino)oct-2-en-4-ol (65). To a solution of Red-Al (0.20 mL, 0.6 mmol) in dry THF (2 mL) was added a solution of alkyne 60 (0.07 g, 0.6 mmol) in dry THF (1 mL) at 0 C̊. The mixture was stirred at room temperature under argon atmosphere for 30 min. The reaction was quenched with sat. potassium sodium tartrate (2 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anh. Na2SO4 , filtered, and concentrated. Purification by column chromatography (silica gel, 10:1 hexane : ethyl acetate) to give E-allylic alcohol 65 (0.06 g, 89%) as a yellow oil. 1H NMR (300 MHz, CDCl3) : δ 7.66-7.22 (m, 20H); 5.76-5.63 (m, 1H); 5.56-5.49 (m,1H); 4.09-4.05(m, 1H); 3.78-3.45 (dd, 2H, J= 13.5 ,84.15); 3.67 (t, 2H, J= 6); 2.78-2.65 (m, 1H); 1.84-1.73 (m,2H); 1.60-1.46 (m, 2H); 1.07 (S, 9H); 13C NMR (75 MHz, CDCl3) δ : 139.79; 135.73; 135.61; 134.81; 134.06; 134.03; 131.64; 131.55; 129.62; 129.40; 129.24; 129.18; 128.56; 128.38; 127.82; 127.71; 127.65; 127.25; 127.12; 126.42; 70.94; 63.86; 61.25; 55.20; 30.31; 27.54; 26.93; 21.37; 19.25; 17.81; [α]D

25.0 -18.64° (c = 0.13, CHCl3); IR (film) 3384, 3027, 2930, 2856, 2360, 1655, 1589, 1471, 1454, 1427, 1258 cm-1.

H�� OH OH

NBn2 (4S,Z)-4-(dibenzylamino)oct-6-ene-1,5-diol (67). To a solution of silyl ether 66 (0.014 g, 0.02 mmol) in dry THF (1 mL) was added TBAF (0.21 ml, 0.21 mmol) at 0 ̊C. The mixture was stirred at room temperature under argon atmosphere for 1 h. The reaction was quenched with sat. NaHCO3 (3 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anh. Na2SO4 , filtered, and concentrated. Purification by column chromatography (silica gel, 4:1 hexane : ethyl acetate) to give the diol (0.008 g, 36% ) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.31-7.19 (m, 10H); 5.76-5.65 (m, 1H); 5.56-5.49 (m,1H) 4.19-4.15 (m, 1H); 3.76-3.56 (dd, 2H, J= 15,48); 3.57(t, 2H, J= 6.3); 2.84-2.70 (m, 1H); 2.79-2.70 (m, 1H); 1.86-1.75 (m, 1H); 1.63-1.52 (m, 2H).

34

NBn Bn OH

(S)-1,1-dibenzyl-2-((R,E)-1-hydroxybut-2-en-1-yl)pyrrolidin-1-ium (70). To a solution of diol 67 ( 0.05 g, 0.015 mmol) in dry CH2Cl2 (20 mL) was added 2,6-lutidine (0.07 mL, 0.59 mmol). The mixture was added Tf2O (0.1 mL, 0.59 mmol) at -78 ̊C and stirred for 1 h. The reaction was quenched with sat. NaHCO3 (20 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anh. NaSO4 , filtered, and concentrated to give the pyrrolidinium ion 70 (0.001 g, 20%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.59-7.25 (m, 10H); 6.07-5.95 (m, 1H); 5.16 (d, 1H, J= 13.5 Hz); 5.06 (d, 1H, J= 13.8 Hz); 4.45 (d, 1H, J= 13.8 Hz); 4.20 (d, 1H, J= 13.8 Hz); 3.50-3.43 (m, 1H); 3.36-3.30 (m, 1H); 3.07-2.97 (m, 1H); 1.68 (d, 3H, J= 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ : 133.49; 133.29; 133.19; 130.90; 130.77; 129.63; 129.56; 129.47; 129.35; 129.19; 129.05; 128.99; 128.12; 127.85; 73.24; 71.03; 64.79; 60.44; 54.97; 30.06; 18.37; 18.13; 17.73; 17.69.

H

O

H

O

NBn2 (S)-2-(dibenzylamino)pentanedial (71). To a solution of oxalyl chloride (0.39 mL, 4.7 mmol) in dry CH2Cl2 (25 mL) at -78 ̊C under argon atmosphere was added dropwise DMSO (0.55 mL, 7.77 mmol) after 30 min, diol 51 (0.31 g, 1.04 mmol) in dry CH2Cl2( 3 mL) was added slowly. The mixture was stirred at -78 ̊C for 1 h.Et3N (1.5 mL, 10.8 mmol) was added at -78 ̊C. The mixture was allowed to warmed to room temperature over 45 min. The reaction was quenched with H2O (30 mL) and extracted with CH2Cl2 ( 3×50 mL). The combined organic layers were dried over anh. Na2SO4 , filtered, and concentrated to give dialdehyde 71 as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 9.73 (s, 1H); 9.69 (s, 1H); 7.35-7.25 (m, 10H); 3.85-3.70 (m, 4H); 3.17 (t, 1H, J= 6.8 Hz); 2.67-2.56 (m, 1H); 2.50-2.39 (m, 1H); 2.04-1.96 (m, 2H); 13C NMR (75 MHz, CDCl3) δ : 203.28; 201.26; 130.39(2C); 129.38(2C); 129.13(2C); 128.88(2C); 128.51(2C); 127.48(2C); 65.96; 54.87; 40.97; 29.72; 16.26.

NH

O

OBn

O

NBn2 (S)-benzyl 5-(but-3-en-1-ylamino)-4-(dibenzylamino)-5-oxopentanoate (77). A solution of carboxylic acid 39 (0.35 g, 0.84 mmol), 3-butenylamine hydrochloride (0.18 g, 1.7 mmol), DMAP (0.02 , 0.17 mmol) and DCC (0.26 g, 1.3 mmol) in dry CH2Cl2 (10 mL) was stirred overnight. The solvent was remove under reduce pressure to give the crude product which was purified by column chromatography to give amide 77 (0.23 g, 60%). 1H NMR (300 MHz, CDCl3) δ : 7.40-7.22 (m, 15H); 5.73-5.60 (m, 1H); 5.23 (d, 1H, J= 14.7 Hz); 5.17 (d, 1H, J= 14.7 Hz); 5.03-4.98 (m, 2H); 3.89 (d, 2H, J= 13.8 Hz); 3.49 (d, 2H, J= 13.8 Hz);

35

3.32 (t, 1H, J= 8.1); 3.27-3.92 (m, 2H); 2.32-2.01 (m, 4H); 0.94-0.86 (m, 2H); 13C NMR (75 MHz, CDCl3) δ : 172.2; 172.2; 139.4; 135.3; 129.0; 128.7; 128.6; 128.5; 128.4; 128.3; 128.0; 127.8; 127.4; 127.1; 126.9; 116.9; 66.2; 60.3; 54.6; 38.4; 33.7; 33.1; 25.5; [α]D

25.0 -72.15° (c = 2.10, CHCl3); IR (film) 3434, 3064, 3055, 2980, 2940, 2847, 1728, 1660, 1519, 1495, 1456, 1211 cm-1

NO O

Bn2N (S)-1-(but-3-en-1-yl)-3-(dibenzylamino)piperidine-2,6-dione (76). To a solution of amide 77 (0.16 g, 0.34 mmol) in dry THF (7 mL) at 0 oC under argon atmosphere was added LAH (0.05 g, 1.3 mmol) and stirred for 30 min. The reaction was quenched with sat. NaHCO3 (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated to give imide 76 as a blue oil. 1H NMR (300 MHz, CDCl3) δ 7.42-7.21 (m, 10H); 5.82-5.69 (m, 1H); 5.03-4.97 (m, 2H); 4.03 (d, 2H, J= 13.9 Hz); 3.83 (t, 2H, J= 6.9 Hz); 3.75 (d, 2H, J= 14.1 Hz); 3.49 (t, 1H, J= 8.1 Hz); 2.79-2.72 (m, 1H); 2.48-2.35 (m, 1H); 2.32-2.25 (m, 2H); 2.06-1.98 (m, 2H) ; 13C NMR (300 MHz, CDCl3) δ 173.3; 171.7; 139.7; 135.2; 128.6; 128.4; 128.2; 127.4; 127.2; 116.9; 59.3; 55.1; 38.8; 32.5; 22.6; [α]D

25.0 -55.44° (c = 1.00, CHCl3); IR (film) 3061, 3029, 2964, 2853, 1726, 1675, 1494, 1455, 1347, 1319 cm-1.

NO OH

Bn2N (3S)-1-(but-3-en-1-yl)-3-(dibenzylamino)-6-hydroxypiperidin-2-one (78). To a solution of imide 76 (0.16 g, 0.34 mmol) in dry toluene (7 mL) at -78 oC under argon atmosphere was added DIBALH (0.68 mL, 0.68 mmol) and stirred for 30 min. The reaction was quenched with MeOH and sat. KNa tartrate (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated to give hydroxylactam 78 as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.46-7.21 (m, 10H); 5.90-5.72 (m, 1H); 5.12-5.03 (m, 2H); 4.89-4.82 (m, 1H); 4.02 (d, 4H, J= 14.0 Hz); 3.71 (d, 4H, J= 14.0 Hz); 3.85-3.69 (m, 1H); 3.48-3.38 (m, 1H); 2.47-2.32 (m, 2H); 2.27-2.18 (m, 1H); 1.97-1.88 (m, 1H); 1.81-1.68 (m, 1H); 1.55-1.42 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.7; 140.2; 135.8; 128.7; 128.6; 127.4; 126.8 (2); 117.3; 80.3; 59.1 55.4; 45.7; 31.6; 29.5; 21.6; IR (film) 3380, 3054, 2984, 2940, 2850, 2641, 1493, 1454 cm-1

36

NHO

OHBn2N

(S)-N-(but-3-en-1-yl)-2-(dibenzylamino)-5-hydroxypentanamide (81). To a solution of imide 76 (0.08 g, 0.22 mmol) in EtOH (4 mL) was added NaBH4 (0.03 g, 0.66 mmol) and the mixture was stirred for 3 hrs. EtOH was removed under reduce pressure. The residue was added acetone and sat. K2CO3 and refluxed for 1 h. The solvent was removed under reduce pressure and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated to give alcohol 81 (0.04 g, 47%) as an yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.50-7.20 (m, 10H); 5.78-5.73 (m, 1H); 5.10 (d, 2H, J= 11.1 Hz); 3.71 (d, 2H, J= 12.6); 3.64-3.50 (m, 2H); 3.38-3.30 (m, 2H); 3.18-3.08 (m, 2H); 2.63 (s, 1H); 2.47-2.20 (m, 2H); 2.00-1.80 (m, 2H); 1.78-1.20 (m, 2H).

NO

Bn2N (3S)-3-(dibenzylamino)-2,3,6,7-tetrahydro-1H-quinolizin-4(9aH)-one (74). To a solution of hydroxylactam 78 (0.096 g, 0.26 mmol) in dry CH2Cl2 (10 mL) at 0 C̊ under argon atmosphere was added TMSOTf (0.11 mL, 0.53 mmol) and stirred for 3 hrs at room temperature. The reaction was quenched with sat. NaHCO3 (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated to give bicyclic compound 74 as an yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.53-7.23 (m, 10H); 5.76-5.67 (m, 2H); 4.90-4.80 (m, 1H); 4.05 (d, 2H, J= 14.0 Hz); 3.77 (d, 2H, J= 14.0 Hz); 3.53-3.24 (m, 3H); 2.34-2.20 (m, 1H); 2.01-1.66 (m, 5H).

O�B�� O

NBn2

OH

(S)-5-(tert-butyldiphenylsilyloxy)-4-(dibenzylamino)pentanoic acid (84). A solution of alcohol 56 (0.3310 g, 0.62 mmol), in acetone (4.0 mL) was treated with Jones reagent at 0oC. The mixture was stirred at 0 ̊C until TLC analysis showed the reaction was complete (ca. 1 h). Isopropanol (0.45 mL) was added slowly dropwise to destroy excess Jones reagent and the mixture was stirred for another 5-10 min until the color of the solution changed to green from red. CH2Cl2 (50 mL) and water (50 mL) wear added. The aqueous phase was extracted with CH2Cl2 (30 mL). The combined organic extracts were washed with water (50 mL) and brine(40 mL) and then dried (Na2SO4), filtered and evaporated in vacuo to give a brown oil which was purified by column chromatography to give carboxylic acid 84 (0.13 g, 36%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.80-7.20 (m, 20H); 4.01-3.69 (AB quartet, 2H,

37

J= 13.27); 3.00-2.98 (m, 1H); 2.46-2.22 (m, 2H); 1.97-1.89 (m 1H); 1.70-1.65 (m, 1H); 1.12 (s, 9H); 13C NMR (75 MHz, CDCl3) δ : 177.85; 137.45; 136.61; 135.68; 135.61; 135.57; 132.94; 132.82; 130.01; 129.95; 129.89; 129.64; 128.58; 128.51; 127.95; 127.90; 127.82; 127.67; 127.56; 127.39; 63.20; 62.88; 59.16; 58.09; 54.25; 44.34; 31.93; 27.57; 23.16; 22.70; 19.1; [α]D

25.0 -10.78° (c = 3.17, CHCl3); IR (film) 3028, 2930, 2857, 1707, 1602, 1589, 1454, 1427, 1265 cm-1.

O�B��

NH

O

NBn2 (S)-N-(but-3-enyl)-5-(tert-butyldiphenylsilyloxy)-4-(dibenzylamino)pentanamide (85). A solution of carboxylic acid 84 (20.9 mg, 0.035 mmol), 3-butenylamine hydrochloride (7.63m g, 0.071 mmol), EDC (0.01 g, 0.053 mmol ) and DMAP ( 0.9 mg, 0.007 mmol) in dry CH2Cl2 (2.8 mL) was stirred overnight. The reaction was quenched with sat. NaHCO3(20 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over anh. Na2SO4 and the solvent was removed under reduced pressure to give the crude product which was purified by column chromatography to give amide 85 (15 mg, 70%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.70-7.19 (m, 20H); 5.75-5.61 (m, 1H); 5.80-4.98 (m, 2H); 3.85-3.60 (AB quartet, 4H, J= 13.6 Hz); 3.87-3.73 (dd, 2H, J=5.3, 20.5 Hz); 3.22-3.00 (m, 2H); 2.76-2.67 (m, 1H); 2.30-2.16 (m, 1H); 2.15-2.06 (q, 2H, J= 13.63 Hz); 2.05-1.96 (m, 1H); 1.14 (s, 9H); 13C NMR (75 MHz, CDCl3) δ : 173.09; 140.67; 135.72; 135.68; 135.38; 133.43; 129.79; 129.00; 128.21; 127.77; 126.83; 116.86; 63.99; 58.22; 54.24; 38.40; 33.94; 33.78; 30.12; 29.72; 29.36; 26.97; 24.99; 19.20; [α]D

25.0 -18.94° (c = 1.40, CHCl3); IR (film) 3300, 3070, 2929, 2856, 1646, 1545, 1453, 1427, 1261 cm-1.

OH

NH

O

NBn2 (S)-N-(but-3-enyl)-4-(dibenzylamino)-5-hydroxypentanamide (83). To a solution of silyl alcohol 85 (57.5 mg, 0.095 mmol) in dry THF at 0 ̊C under argon atmosphere was added TBAF (0.09 mL, 0.095 mmol) and stirred for 1 h. The reaction was quenched with sat.NaHCO3(20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated to give alcohol 83 ( 26.1 mg, 75%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.5-7.2 (m, 10H); 5.8-5.65 (m, 1H); 5.13-5.02 (m, 2H); 3.85-3.56 (AB quartet, 4H, J= 13.2 Hz); 3.52-3.50 (d, 2H, J= 4.8 Hz); 3.31-3.23 (q, 2H, J= 12.66 H); 2.80-2.65 (m, 1H); 2.50-2.00 (m, 1H); 1.65-1.49 (m, 2H); 13C NMR (75 MHz, CDCl3) δ : 135.19; 129.80; 128.88; 128.28; 117.12; 66.68; 60.43; 53.49; 38.82; 33.58; 29.72; 21.67; [α]D

25.0 +30.30° (c = 1.45, CHCl3); IR (film) 3299, 3062, 2934, 2360, 1621, 1493

38

O O

NBn2

NH

H

(S)-N-(but-3-enyl)-4-(dibenzylamino)-5-oxopentanamide (86). To a solution of oxalyl chloride ( 0.025 mL, 0.29 mmol ) in dry CH2Cl2 ( 2.7 mL) at -78 ̊C under argon atmosphere was added dropwise DMSO (0.04 mL, 0.59 mmol). After 30 min, alcohol 83 (36.4 mg, 0.099 mmol ) in CH2Cl2 ( 0.27 mL) was added slowly. The mixture was stirred at -78 ̊C for 1 h. Et3N (0.12 mL, 0.89 mmol) was added at -78 ̊C and the mixture was allowed to warm to room temperature over 45 minutes. The reaction was quenched with water and extracted with CH2Cl2 (3×70 mL). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated to give aldehyde 86 (36.0 mg, quantitative) as a yellow oil. The aldehyde is the major component in equilibrium with the corresponding hydroxylactam. 1H NMR (300 MHz, CDCl3) δ : 7.50-7.20 (m, 10H); 5.90-5.72 (m, 1H); 5.12-5.03 (m, 2H); 4.89-4.82 (m, 1H); 4.02 (d, 2H, J= 14.0 Hz); 3.71 (d, 2H, J= 14.0 Hz); 3.85-3.69 (m, 1H); 3.48-3.38 (m, 1H); 2.47-2.32 (m, 2H); 2.27-2.18 (m, 1H); 1.97-1.88 (m, 1H); 1.81-1.68 (m, 1H); 1.55-1.42 (m, 1H); 13C NMR (75 MHz, CDCl3) δ :171.7; 140.2; 135.8; 128.7; 128.6; 128.2; 127.4; 126.8; 117.3; 80.3; 59.1; 55.4; 45.7; 31.6; 29.5; 21.6; [α]D

25.0 -80.45° (c = 1.85, CHCl3).

N

NBn2

O

H

(1S,9aS)-1-(dibenzylamino)-2,3,9,9a-tetrahydro-1H-quinolizin-4(6H)-one (74). To a solution of aldehyde 86 (36.0 mg, 0.1 mmol) in CH2Cl2 under argon atmosphere at 0oC was added TMSOTf (30 μL, 0.3 mmol). The mixture was allowed to warm to room temperature and stirred for 3h. The reaction was quenched with NaHCO3 (30 mL) and extracted with CH2Cl2 (3×30 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated to give the desired dibenzylamino quinolizidinone (27.4 mg, 75%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.43-7.17 (m, 10H); 5.78-5.65 (m, 2H); 4.92-4.82 (m, 1H); 4.08 (d, 2H, J= 14.0 Hz); 3.76 (d, 2H, J= 14.0 Hz); 3.53-3.24 (m, 3H); 2.34-2.24 (m, 1H); 2.02-1.65 (m, 5H). [α]D

25.0 +19.05° (c = 0.05, CHCl3); IR (film) 2924, 2853, 1731, 1639, 1455, 1376 cm-1.

HO

O

OBn

O

NBn2

(S)-5-(benzyloxy)-4-(dibenzylamino)-5-oxopentanoic acid (87). 1H NMR (300 MHz, CDCl3) δ : 7.50-7.20 (m, 15H); 5.01 (s, 2H); 3.82 (d, 2H, J= 13.2 Hz); 3.81 (s, 1H); 3.73 (d, 2H, J= 13.5 Hz); 3.43-3.40 (m, 1H); 2.62-2.57 (m, 1H); 2.17-2.14 (m, 2H).

39

NH

O

OBn

O

NBn2

(S)-benzyl 5-(but-3-enylamino)-2-(dibenzylamino)-5-oxopentanoate (88). A solution of benzyl ester 87 (0.22 g, 0.48 mmol), 3-butenylamine hydrochloride (0.11 g, 0.96 mmol), DMAP (0.01, 0.10 mmol) and DCC (0.16 g, 0.72 mmol) in dry CH2Cl2 (15 mL) was stirred overnight. The solvent was remove under reduce pressure to give the crude product which was purified by column chromatography to give amide 88 as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.29-7.19 (m, 1H); 5.76-5.63 (m, 1H); 5.05-5.01 (m, 4H); 3.62(d, 2H, J= 13.5 Hz); 3.53 (d, 2H, J= 13.8 Hz); 3.29-3.19 (m, 2H); 3.02-2.98 (m, 1H); 2.74-2.63 (m, 1H); 2.42-2.32 (m, 1H); 2.19-2.16 (m, 2H); 2.07-2.02 (m, 2H).

N

O

OBn

O

NBn2OO

(S)-benzyl 5-(tert-butoxycarbonyl)-2-(dibenzylamino)-5-oxopentanoate (89). A solution of amide 88 (0.027 g, 0.04 mmol), DMAP (0.001 mg, 0.008 mmol), (Boc)2O (0.11g, 0.51 mmol) and Et3N (0.05 mL, 0.36 mmol) in dry CH2Cl2 (3.0 mL) was stirred 3h. The reaction was quenched with sat.NaHCO3(3.0 mL) and extracted with CH2Cl2 (3×5.0 mL). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated to give protected amide 89 (0.013 g, 53%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 7.27-7.15 (m, 15H); 5.80-5.66 (m, 1H); 5.05-4.96 (m, 4H); 3.97 (d, 2H, J= 14.4 Hz); 3.76-3.56 (m, 2H); 3.47 (d, 2H, J= 14.4 Hz); 2.74 (m, 1H); 2.28-2.26 (m, 2H); 2.05-2.03 (m, 2H); 1.23 (s, 9H).

N

O

H

O

NBn2OO

(S)-tert-butyl but-3-enyl(4-(dibenzylamino)-5-oxopentanoyl)carbamate (90). A solution

of protected amide 89 (12.9 mg, 0.04 mmol) in dry CH2Cl2 (3.00 mL) at -78 ̊C under argon atmosphere was added DIBALH (0.05 mL, 0.047 mmol). The mixture was stirred at -78 ̊C for 30 min. The mixture was quenched with sat.NaHCO3(3.0 mL) and extracted with CH2Cl2 (3×5.0 mL). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated to give aldehyde 90 (10.5 mg, 99%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ : 9.60 (s, 1H); 7.32-7.18 (m, 10H); 5.55-5.39 (m, 2H); 4.87-4.80 (m, 2H); 3.81 (d, 2H, J= 13.5 Hz); 3.50 (d, 2H, J= 13.6 Hz);2.85-2.73 (m, 1H); 2.64-2.50 (m, 2H); 2.45-2.40 (m, 2H); 2.20-2.09 (m, 2H); 2.02-1.98 (m, 1H); 1.40 (s, 9H).

40

REFFERENCES

[1] Wink, M. (1987) Planta medica. n.p.

[2] Fitch, Richard W., and others. (2003). “Bioassay-guided isolation of Epiquinamide, a

novel quinolizidine alkaloid and nicotinic agonist from an Ecuadorian poison

frog, Epidobates tricolor.” J. Nat. Prod., 66,10: 1345-1350.

[3] Fitch, Richard W., and others. (2009). “Epiquinamide : a poison that wasn’t from a frog

that was.” J. Nat. Prod., 72, 2: 243-247.

[4] Wijdeven, Marloes A., and others. (2005). “Total synthesis of (+)-Epiquinamide.” Org.

Lett., 7, 18: 4005-4007.

[5] Kanakubo, A., and others (2006). “The synthesis and nicotinic binding activity of (±)-

epiquinamide and (±)-C(1)-epiepiquinamide.” Bioorg. Med. Chem. Lett., 16, 17

(September): 4648-4651.

[6] Suyama, Takashi L., and William H. Gerwick. (2006). “Practical total synthesis of

Epiquinamide enantiomers.” Org. Lett., 8, 20: 4541-4543.

[7] Ghosh, S., and J. Shashidhar. (2009). “Total synthesis of (+)-epiquinamide from D-

mannitol.” Tetrahedron Lett. 50 (March): 1177-1179.

[8] Badorrey, R., and others. (1997). “A convenient synthesis of L-α-vinylglycine from D-

mannitol.” Synthesis, 7: 747-749.

[9] Madhan, A., and B.Venkateswara Rao. (2003).”Stereoselective synthesis of 1,4-dideoxy-

1,4-immino-D-allitol and formal synthesis of (2S, 3R, 4S)-3,4-dihydroxyproline.”

Tetrahedron Lett., 44, 30: 5641-564.

[10] Badorrey, R., and others. (2003). “Study of the reaction between vinyl magnesium

bromide and imines derived from (R)-glyceraldehyde-The key step in the

stereodivergent synthsis of conveniently protected, enantiopure syn- and anti-2-

amino-1,3,4-butenetriol derivative.”Eur, J. Org.Chem.: 2268-2275.

[11] Wijdeven, Marloes A., and others. (2008). “N,N-acetyls as N-acyliminium ion precursors

41

: synthesis and absolute stereochemistry of Epiquinamide.” Org. Lett. 10: 4001-

4003.

[12] Huang Pei-Qiang, Zheng-Qing Guo, and ; Yaun-Ping Ruan. (2006). “A versatile

approach for the asymmetric synthesis of (1R, 9aR)-Epiquinamide and (1R, 9aR)-

Homopumilitoxin 223G.” Org.Lett., 8, 7: 1435-1438.

[13] Chandrasekhar, S., Bibhuti Bhusan Parida, and Ch. Rambabu. (2009). “Stereoflexible

total synthesis of (-)-epiquinamide.” Tetrahedron Letters, 50, 26: 3294-3295.

[14] Corey, E. J., and others. (1999). “Enantioselective total synthesis of Aspidophytine.” J.

Am. Chem. Soc., 121, 28: 6771-6772.

Appendix

43

1H NMR and 13C NMR spectra of compounds

Page

Compound 53 1H NMR spectrum………………………………………………… 46 Compound 53 13C NMR spectrum………………………………………….………. 47 Compound 51 1H NMR spectrum………………………………………………… 48 Compound 51 13C NMR spectrum………………………………………….………. 49 Compound 54 1H NMR spectrum………………………………………….………. 50 Compound 54 13C NMR spectrum………………………………………….………. 51 Compound 56 1H NMR spectrum………………………………………….………. 52 Compound 56 13C NMR spectrum………………………………………….………. 53 Compound 57 1H NMR spectrum………………………………………….………. 54 Compound 59 1H NMR spectrum………………………………………….………. 55 Compound 59 13C NMR spectrum………………………………………….………. 56 Compound 60 1H NMR spectrum………………………………………….………. 57 Compound 60 13C NMR spectrum………………………………………….………. 58 Compound 61 1H NMR spectrum………………………………………….………. 59 Compound 62 1H NMR spectrum………………………………………….………. 60 Compound 62 13C NMR spectrum………………………………………….………. 61 Compound 63 1H NMR spectrum………………………………………….………. 62 Compound 64 13C NMR spectrum………………………………………….………. 63 Compound 65 1H NMR spectrum………………………………………….………. 64 Compound 65 13C NMR spectrum………………………………………….………. 65 Compound 66 1H NMR spectrum………………………………………….………. 66 Compound 66 13C NMR spectrum………………………………………….………. 67 Compound 67 1H NMR spectrum………………………………………….………. 68 Compound 70 1H NMR spectrum………………………………………….………. 69

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Page Compound 70 13C NMR spectrum………………………………………….………. 70 Compound 71 1H NMR spectrum………………………………………….………. 71 Compound 71 13C NMR spectrum………………………………………….………. 72 Compound 80 1H NMR spectrum………………………………………….………. 73 Compound 80 13C NMR spectrum………………………………………….………. 74 Compound 77 1H NMR spectrum………………………………………….………. 75 Compound 77 13C NMR spectrum………………………………………….………. 76 Compound 76 1H NMR spectrum………………………………………….………. 77 Compound 76 13C NMR spectrum………………………………………….………. 78 Compound 78 1H NMR spectrum………………………………………….………. 79 Compound 78 13C NMR spectrum………………………………………….………. 80 Compound 81 1H NMR spectrum………………………………………….………. 81 Compound 84 1H NMR spectrum………………………………………….………. 82 Compound 84 13C NMR spectrum………………………………………….………. 83 Compound 85 1H NMR spectrum………………………………………….………. 84 Compound 85 13C NMR spectrum………………………………………….………. 85 Compound 83 1H NMR spectrum………………………………………….………. 86 Compound 83 13C NMR spectrum………………………………………….………. 87 Compound 86 1H NMR spectrum………………………………………….………. 88 Compound 86 13C NMR spectrum………………………………………….………. 89 Compound 74 1H NMR spectrum………………………………………….………. 90 Compound 74 13C NMR spectrum………………………………………….………. 91 Compound 87 1H NMR spectrum………………………………………….………. 92 Compound 88 1H NMR spectrum………………………………………….………. 93 Compound 89 1H NMR spectrum………………………………………….………. 94

45

Page

Compound 90 1H NMR spectrum………………………………………….………. 95

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1H NMR spectrum of Compound 53

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13C NMR spectrum of Compound 53

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Biography Name Miss. Chitlada Hemmara

ชือ-สกุล นางสาว จิตรลดา เหมรา E-mail address [email protected] Address 8 M.9, Kudee District, Ampur Phakhai, Ayuthaya, Thailand, 13120 Education

2005 – 2009 Bachelor of Science (Chemistry), Silpakorn University,

Thailand

2010 – 2012 Master of Science (Organic Chemistry), Silpakorn University, Thailand

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