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Hindawi Publishing CorporationISRN Organic ChemistryVolume 2013 Article ID 292396 14 pageshttpdxdoiorg1011552013292396

Review ArticleGoniomitine An Overview on the Chemistry ofThis Indole Alkaloid

Joseacute C F Alves

Instituto de Pesquisas de Produtos Naturais Walter Mors Centro de Ciencias da Saude Bloco HUniversidade Federal do Rio de Janeiro 21941-902 Rio de Janeiro RJ Brazil

Correspondence should be addressed to Jose C F Alves alvesjcfyahoocombr

Received 20 September 2013 Accepted 22 October 2013

Academic Editors G Li F Machetti and J Wu

Copyright copy 2013 Jose C F Alves This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

This paper reports an overview on the chemistry of the indole alkaloid goniomitine focusing mainly on the methods of synthesisrelated to this natural product and analogs

1 Introduction

The indole alkaloids belong to the class of natural substancesdisplaying biological activities as well as a broad structuraldiversity In view of these important properties these prod-ucts are target of study in the areas of isolation identificationand synthesis [1ndash5] Goniomitine (1) (Figure 1) is an indolealkaloid that was isolated and identified by Randriambolaet al [6] and Hashimoto and Husson [7] The uniquestructure and biological activity of goniomitine have attractedthe attention of several groups This review describes theisolation biogenesis hypothesis chemical transformationsand syntheses of this alkaloid and analogs

2 Isolation of Goniomitine

In the course of studies of the alkaloids of the genusGonioma Randriambola et al [6] isolated from the rootbark of Gonioma malagasy a crystalline compound namedgoniomitine with melting point of 150∘C (ether-methanol)[120572]D20

minus80∘ (c 09 in CHCl3) and molecular formula

C19H26N2O (HRMS M+∙ 2982080 calculated for 2982045)

The structure of goniomitine was initially proposed as indi-cated in Figure 1 with 20S 21R configuration based on itsNMR spectra Its absolute structure was deduced through thecorrelation with other alkaloids from Aspidosperma found in

the same plant from where goniomitine had been isolatedThe relative structure of goniomitine (1) was soon after con-firmed by Takano et al [8] through the total enantioselectivesynthesis of the natural form of this alkaloid It could beevidenced that the absolute structure of the compound 1 isenantiomeric to the one that had been initially proposed for20S 21R configuration

3 Biogenesis of Goniomitine

Randriambola et al [6] proposed that goniomitine (1) may bederived from the Aspidosperma skeleton of vincadifformine(2) by the successive steps depicted in Scheme 1

4 Chemical Transformations andSyntheses of Goniomitine and Analogs

41 Chemical Transformations of Goniomitine For the occa-sion of the structural determination of goniomitine (1) [6]this compound was transformed into the N-acetyl derivative5 upon treatment with Ac

2O in MeOH and into the NO-

diacetyl derivative 6 upon treatment with Ac2O in pyridine

(Scheme 2) The formation of the acetylated compounds 5and 6 confirmed the presence of the groups OH and NH inthe structure of 1

2 ISRN Organic Chemistry

OH

N

N

H

H

S21

R20

OH

N

N

H

H

S21R

20

(unnatural)(20S 21R)-(+)-Goniomitine (1)

(natural)(20R 21S)-(minus)-Goniomitine (1)

Figure 1 Natural (minus)- and unnatural (+)-goniomitine (1)

c

d

NH

N

H

1 2

34

56

789

10

1112

13

1415

1617 18

192021

CO2Me

a-b

N

N

H

H

HHO

+ NH

NHHO +

N

NH

H

+

OH

N

NH

H

12

34

56

78910

1112

13

14

15

16

17 181920

21

OH

1

2 3 44

Scheme 1 Biogenetic hypothesis of transformation of vincadifformine (2) into goniomitine (1) (a) oxidative fission of the C-5 N-4 bond (b)decarboxylation (c) retro-Mannich reaction (d) nucleophilic attack of the indole nitrogen on the iminium moiety

N

NHH

OH

N

NH

OH

Ac

Ac2O Ac2OMeOH Py

N

NH

Ac

OAc

15 6

Scheme 2 Chemical transformations of goniomitine (1) into the acetyl derivatives 5 and 6

ISRN Organic Chemistry 3

NH

N

NH

N

NH

N

NH

N

I

a b c d

e

N H

CH3

TMS

(55) (57)

OH

(97)

OH OH

(91)

Me Me

(59)

+

minus

N

NH

OH

Me

+

(36 23)

(+minus)-12

7 8 9 10 11

11

Scheme 3 Reagents and conditions (a) (i) n-BuLi (22 equiv) hexane (reflux 6 h) and (ii) methyl 3-(3-pyridyl)propanoate THF (minus78 to15∘C) (b) MeMgI (10 equiv) ethylene oxide (10 equiv) Et

2

O (1 h) reflux (2 h) (c) MeI CH2

Cl2

(reflux 2 h) (d) H2

PtO2

MeOH (3 h) (e)H2

PtO2

NaOMe MeOH (3 h)

42 Synthesis of the Goniomitine Analog (+minus)-12 In orderto ascertain unambiguously the unprecedented structure ofthe alkaloid goniomitine (1) Hashimoto and Husson [7]synthesized the goniomitine analog (+minus)-12 by the sequenceof reactions depicted in Scheme 3

43 Total Synthesis of (minus)-Goniomitine by Takano The firstenantiocontrolled total synthesis of natural (minus)-goniomitine(1) was published in 1991 by Takano et al [8] who estab-lished the absolute stereochemistry of this alkaloid Thistotal synthesis depicted in Scheme 4 starts with the chiralcyclopentadienone synthon (minus)-13

44The First Biomimetic Approach to the Skeleton of Goniomi-tine from an Aspidosperma Alkaloid The results from thestudy of biomimetic transformation of an Aspidospermaalkaloid (2) into the substances 39-40 with the skeletonof goniomitine (1) were published in 1995 by Lewin et al[9] The sequences of reactions for the discovery of a newbiomimetic in vitro rearrangement are depicted in Scheme 5Scheme 6 displays the proposed mechanism [9] for thetransformation of compound 36 into the alkaloids 39 and40

45 Semisynthesis of (+)-(16S20S21R)-16-Hydroxymethyl-goniomitine from (minus)-Vincadifformine In continuation tothe studies of chemical transformations of vincadifformine(2) into alkaloids analogs to goniomitine (1) Lewin andSchaeffer [10] published in 1995 the semisynthesis of (+)-16-hydroxymethyl-goniomitine (45)This alkaloid was obtained

as a result of the attempts to synthesize (+)-goniomitine(1) from the compound 40 previously obtained from (minus)-vincadifformine (2) (Scheme 5) [9] In Scheme 7 are depictedthe sequences of reactions that led to the synthesis of com-pound 45 as well as other alkaloids with tetracyclic skeletonof goniomitine (1)

46 Synthesis of the Goniomitine Analogs 52ndash55 by Cycload-dition Reactions In the year 1996 Gurtler et al [11] pub-lished the synthesis of the goniomitine analogs 52ndash55 by[4 + 2] cycloaddition reactions between 2-vinylindolesand substituted cyclic enamines via anodic oxidation(Scheme 8)

47 Proposal of Synthesis of Goniomitine by Alves In the year2000 Alves [12] presented his qualification exam of doctorateabout a plan of synthesis of the indole alkaloid goniomitine(1) The convergent strategies and synthetic routes for thesynthesis of this alkaloid idealized on that occasion aredescribed in the supplementary material of this reviewavailable online at httpdxdoiorg1011552013292396

48 Syntheses of Cytotoxic Bisindole Alkaloids In the year2000 Lewin et al [13] published an article about a slightmod-ification of the Borch reductive amination method (delayedaddition of NaBH

3CN) [14 15] applied to compound 40

analog of the natural alkaloid goniomitine (1) As a result ofthis reaction a series of new cytotoxic bisindole alkaloids wasprepared as depicted in Scheme 9


O

HH

O

HH O O

S

S

O

SS

O

HO

O

d

i

NH

O

I

NH

O

N

O

NH

O

N

O

NH

H

O

NH

N NH

m

t

u

21

z

y

NH

O NH

O

N

NH

O

q

l

a-c(53)

(minus)-13

e-f

g-h (75)

MeOMeOMeO j-k

OEt

OEt

(81)

CO2Me

(81)

OMe

(11 70)

+

n-p

NH2

HN

HN

HNHN

HN HN HN

r-s

CN

CN CN

Cl minus +

v-x

OH

(82)31 C21-H120573

(minus)-1 C21-H120572

15 16

171819

21 2322

24

28 29 30

27 26 25

14

20

(82 rArr 17)

(78 rArr 25) (65 rArr 23)

(84 rArr 27) (40 rArr 29)

(72 rArr 14)

Scheme 4 Reagents and conditions (a) Zn (50 equiv) AcOH-EtOH (1 3) reflux (4 h) (b) EtI (20 equiv) t-BuOK (12 equiv) THF (minus70 tominus30∘C 15min) (c) allyl bromide (20 equiv) t-BuOK (12 equiv) THF (minus30∘C 5min) (d) o-dichlorobenzene (reflux 24 h) (e) LiAlH

4

(10equiv) CuI (05 equiv) HMPA-THF (1 4) minus75∘C (15min) (f) propane-13-diyldithiotosylate (15 equiv) t-BuOK (30 equiv) t-BuOH-THF(1 4) 0∘C (g) KOH (50 equiv) t-BuOH (70∘C 12 h) (h) CH

2

N2

Et2

O (i) MeI (10 equiv) CaCO3

(50 equiv) 10 aq MeCN (reflux 1 h)(j) Ph

3

P (40 equiv) CBr4

(20 equiv) Et3

N (30 equiv) CH2

Cl2

(0∘C 5min) (k) LDA (30 equiv) THF (minus78∘C 10min) (l) compound 20 (11equiv) PdCl

2

(PPh3

)2

(2) CuI (5) Et3

N (reflux 30min) (m) NaOEt (10 equiv) Et3

N (5) EtOH (reflux 3 h) (n) (i) dicyclohexylborane(15 equiv) THF (0∘C 30min) (ii) 10 NaOH (10 equiv) 30 H

2

O2

(30 equiv) 0∘C (30min) (o) phthalimide (13 equiv) Ph3

P (13 equiv)(i-PrO

2

CN)2

(13 equiv) THF (0∘C 10min) (p) NH2

NH2

sdotH2

O (40 equiv) EtOH (reflux 2 h) (q) [Me2

N=CH2

]Cl (15 equiv) CH2

Cl2

(rt30min) (r) MeI MeOH (rt 10min) (s) NaCN (13 equiv) DMF (100∘C 10min) (t) POCl

3

(60 equiv) toluene (reflux 2 h) (u) NaBH4

MeOH 0∘C (v) DIBAL (15 equiv) CH

2

Cl2

(minus75∘C 10min) (x) dil H2

SO4

(y) NaBH4

(z) 30 HCl-MeOH (1 10) reflux (30min)


N

N

H

OO

O

N

N

H

OO

O

N

N

H

N

N

H

O

N

N

Cl Cl Cl

ClCl

H

N

NH

O

NH

N

H

OO

O

N

N

H

O

N

NH

NH

N

H

5 5

55b

a

5

c

5

d

e

f

g

h

CO2Me CO2Me CO2Me CO2Me

CO2MeCO2Me

CO2MeCO2Me

CO2Me

3 steps

MeO

(82)

+ Ar

Ar

Ar

Ar = m-Cl-C6H4

(71)

12057235a C5-H12057335b C5-H (3 1)

(100)

(18)

HO

HO

HO

(53)

CHOCHO

+

(42 11)

(40)

(52)

(48)

2 32 33 34

36

37

38

40 39

Scheme 5 Reagents and conditions (a)m-CPBA (11 equiv) CH2

Cl2

(rt 3 h) (b) 02mol Lminus1 NaOH-MeOH (rt 5min) (c) NaI (30 equiv)AcOH (rt 15 h) (d) 11 mol Lminus1 HCl (105∘C 10min) (e) TFA (16 equiv) CH

2

Cl2

(rt 20min) (f) TFA (rt 4 h) (g) TFA (16 equiv) CH2

Cl2

(rt 15 h) (h) TFA (125 equiv) CH2

Cl2

(rt 45 h)

In continuation to the studies of synthesis of cytotoxicbisindole alkaloids Raoul et al [16] published in the year2001 an article with a novel series of these alkaloids pre-pared by reductive amination of the compound 40 withvarious anilines using the modified Borch amination con-ditions described in Scheme 9 (delayed addition (20min) ofNaBH

3CN) [15] The influence of substitution of the starting

aniline on the reaction and on cytotoxicity of produceddimers is discussed in the paper

49 Total Synthesis of (+minus)-Goniomitine by Pagenkopf In theyear 2008 Morales and Pagenkopf [17] published the total

synthesis of racemic (+minus)-goniomitine (1) accomplishedin 17 linear steps with 52 overall yield starting fromcommercially available 120575-valerolactam (65) Their syntheticapproach includes the application of a formal [3+2] cycload-dition between the highly functionalized nitrile 68 and theactivated cyclopropane 69 to prepare the indole nucleus(Scheme 10)

410 Total Synthesis of (+minus)-Goniomitine by Waser DeSimone et al [18] published the synthesis of racemic goniomi-tine (1) with the first study of its bioactivity revealingsignificant cytotoxicity against several cancer cell lines [18


N

N

Cl

O

H TFA

TFA

N

N

Cl Cl

ClHO

OHCH

N

NH

O

N

NOOHC

H

N

NH

O

CHO

CHOCHOCHO

CHO CHO CHO

N

N

H

O

H

N

NH

N

NO

N

NH

O

H N

NH

a

b

b

a

HO

HO HO

CO2Me CO2Me CO2Me

CO2Me

CO2MeCO2MeCO2Me

CO2Me CO2Me CO2Me

CH2Cl2

+

+

minus

minus

+minus

+

minus

+

minus

OCOCF3

36

39

36a 36b 36b

36c36d

39a 39b 40

Scheme 6

N

NH

HO

HO

HO

HO

HO

CHO

N

NH

N

NH

H

N

NH

N

NH

N

NH

H

H N

NH

H

a b

c

d e f

CO2Me CO2Me

(62)

OH OH

OHOHOHOH

OH OH OH

(43)

CO2H

CH3

(75)(66)(35)

(57)

40 41 42

43 44 45 46

Scheme 7 Reagents and conditions (a) NaBH3

CN AcOH (rt 15 h) (b) NaOH-MeOH (120∘C 1 h) (c) LiAlH4

(excess) THF (reflux 3 h)(d) H

2

(1 atm) 10 Pd-C MeOH (rt 5 h) (e) TiCl3

-H2

O MeOH (rt 20 h) (f) 30 HCl-MeOH (120∘C 15 h)


N

NH

CN

CNMe

H

OEt

N

NHH

N

Me

Me

NH

CN

HNH

CN

N

Me

Me

Me

Me

Me N

CN

CN

CN

H

a

b

c

d

N

CO2Me

R2

R1 R3

(62)

+(68)

49 R2 = H R3 = CN50 R2 = H R3 = CO2Me51 R2 = Me R3 = CO2Me

(53)

(91)

47 R1 = Me48 R1 = (CH2)2OEt

CO2Me

55

52

53

54

Scheme 8 Reagents and conditions (a) vinylindole 47 (10 equiv) enamine 49 (237 equiv) CH3

CN LiClO4

(01mol Lminus1) electrolysis(480mV versusAgAgNO

3

current (20 to 2mA) 200min) (b) vinylindole 48 (10 equiv) enamine 49 (617 equiv) CH3

CN LiClO4

(01molLminus1) electrolysis (480mV versus AgAgNO

3

current (20 to 2mA) 200min) (c) vinylindole 47 (10 equiv) enamine 50 (14 equiv) CH3

CNLiClO

4

(01mol Lminus1) electrolysis (480mV versus AgAgNO3

current (20 to 2mA) 40min) (d) vinylindole 47 (10 equiv) enamine 51 (21equiv) CH

3

CN LiClO4


current (20 to 2mA) 200min)

19] The strategy of this synthesis is based on cyclizationof aminocyclopropanes [20] applied to cyclopropyl ketone83 to lead to compound 84 with tetracyclic skeleton ofgoniomitine (Scheme 11)

411 Total Syntheses of (+minus)- (minus)- and (+)-Goniomitine byMukay In the year 2011 Mizutani et al [21] published thesyntheses of both racemic and optically active goniomitinewhose principal steps are the preparation of the indole skele-ton by their own developed procedure [22] and alkene cross-metathesis The synthesis of racemic (+minus)-goniomitine (1)was performed as a preliminary study by the sequence ofreactions depicted in Scheme 12

The convergent total synthesis of the natural (minus)-goni-omitine (1) [21] was completed by the sequence of reactionsdepicted in Scheme 13

Using the synthetic route described in Scheme 13 butstarting from the enantiomer of the lactam 97 (ent-97)Mizu-tani et al [21] synthesized the unnatural (+)-goniomitine(ent-1)With the racemic natural and unnatural goniomitinein hand the authors [21] executed the preliminary bioactiveassays which revealed that natural (minus)-goniomitine hasstronger antiproliferative activity inMock andMDCKMDR1cells than its enantiomer

412 Total Synthesis of (+minus)-Goniomitine by Bach In theyear 2012 Jiao et al [23] published the total synthesis ofracemic goniomitine (1) using the strategy of C-2 alkyla-tion of indoles catalyzed by palladium via a norbornene-mediated CndashH activation [24] The steps for the synthesisof (+minus)-goniomitine (1) by this strategy are depicted inScheme 14


N

NH

AcO

HN

HN

HN

HN

HN

NNH

AcO

N

NH

N

NH

NNH

N

NH

H

NNH

H

N

NH

N

NNH

Ac

Ac

Ac

Ac

Ac

N

NH

NN

N

NH

HO

HN

NNH

HO

OH

OH

N

NH

CHO

N

NH

HO

N

NNH

HO

HO

HOHOHO

Me

ab

c

d

ef

g

MeO2C

MeO2C

MeO2C

MeO2CMeO2C

CO2Me CO2Me

CO2Me

CO2Me

CO2MeCO2Me

CO2MeCO2Me

(64)

MeO2C

(68)

Ph

+

+

+

(23 28)

(51)(45)

(38)(70

)

(48 22)

(32)

40 56 57

58

58

59

6061

6263

64

NH2 middot HCl

Scheme 9 Reagents and conditions (a) compound 56 (50 equiv) NaBH3

CN (immediate addition) MeOH (rt 16 h) (b) compound 56 (50equiv) NaBH

3

CN (delayed addition 20min) MeOH (rt 16 h) (c) TiCl3

-H2

O (60 equiv) MeOH (rt 20 h) (d) Ac2

O Py (rt 48 h) (e)Ac2

O Py (rt 3 h) (f) CH2

O NaBH3

CN AcOH (rt 2 h) (g) LiAlH4

THF (reflux 3 h)


N

O

NH

NH

O

NH

NH

OCN

N

CN

HN HN HN

H

N

OBn

Bn

BnBn

X

NH

NH

N

O

NH

N

OBn

CN

OMe

NH

NH

N

O

NH

N

O

a

f

g

hi

j j

i

k

l m

2021 21 21

20 20

R 2R1

b c(828)

(83) 65 R1 = R2 = H66 R1 = Et R2 = Bn

+

d e(70) 67 X = OH

68 X = CN

CO2Et

CO2Et

CO2Et

(74)

(98)

(75)(97)

(trace)

(97)

(70)

(70)

(44)

OH OH

(79)

(+minus)-Goniomitine (1)

69 70

717225

27 73

29 31

Scheme 10 Reagents and conditions (a) (i) n-BuLi (20 equiv) THF (minus78∘C) (ii) EtI (10 equiv) minus78∘C (1 h) (iii) BnBr (10 equiv) rt(overnight) (b) (i) LDA (10 equiv) THF (minus78∘C 15min) (ii) BrCH

2

CH2

OTHP (11 equiv) rt (overnight) (c) TsOH (01 equiv) MeOH (ice-brine bath 4 h) (d) Et

3

N (21 equiv)MsCl (10 equiv) CH2

Cl2

(0∘C to rt 3 h) (e) NaCN (20 equiv)MeCN 120∘C (120583w 8 h 900 rpm stirring)(f) Nitrile 68 (10 equiv) cyclopropane 69 (29 equiv) TMSOTf (10 equiv) EtNO

2

(minus30∘C 24 h) (g) 5 Pd-C (003 equiv) mesitylene (reflux24 h) (h) NaOH (10 equiv) EtOH-H

2

O (1 1) 150∘C (120583w 3 h 900 rpm stirring) (i) Na (50 equiv) liq NH3

(0042mol Lminus1) THF (minus78∘C10min) (j) (i) [Me

2

N=CH2

]Cl (15 equiv) CH2

Cl2

(rt 15min) (ii) MeI (40 equiv) MeOH (rt 10min) (iii) NaCN (13 equiv) DMF (100∘C10min) (k) (i) POCl

3

(60 equiv) toluene (reflux 2 h) (ii) NaBH4

(20 equiv) MeOH (0∘C 30min) (l) (i) DIBAL (15 equiv) CH2

Cl2

(minus78∘C10min) (ii) 075mol Lminus1 H

2

SO4

(iii) NaBH4

(22 equiv) EtOH (0∘C 30min) (m) TsOH (cat) Et3

N-MeOH (3 5 vv) reflux (30min)

413 Synthesis of (+)- and (minus)-Goniomitine by Lewin Inthe year 2013 Lewin et al [25] have published the firstbiomimetic semisynthesis of goniomitine (1) in nine stepswith 11 overall yield starting from vincadifformine (2)Natural (minus)- and unnatural (+)-goniomitine were preparedfrom (+)- and (minus)-vincadifformine respectivelyThe steps forthe synthesis of unnatural (+)-goniomitine (1) are depicted inScheme 15

Lewin et al [25] have synthesized the natural (minus)-goni-omitine (1) starting from (+)-vincadifformine (ent-2) using

the same conditions described in Scheme 15 The evaluationof the antiproliferative effect of (+)- and (minus)-goniomitine (1)undertaken on five human cancer cell lines has demonstratedthat unnatural (+)-goniomitine is more potent than itsenantiomer (minus)-goniomitine [25] in opposition to Mizutaniet alrsquos results on a canine kidney cell line (MDCK II) [21]

414 Synthesis of (+minus)-Goniomitine by Zhu In the year2013 Xu et al [26] have published a seven-step totalsynthesis of (+minus)-goniomitine (1) through two key steps


N OH

N O N N O N OH N

N

OH

NH

NH

N

NH

O

NH

N

NH

O

N

NH

H

a b c d e

hf g

ij

(67)

Cbz Cbz Cbz Cbz

CbzCbz

Cbz

(93) (76)OEt

(91)OH

OH

OH

(93) OMe

Me

(48)

OTIPSOTIPS

OTIPS OTIPS

COOH

(100)

(77) (93)

H+

74 75 76 77 78 79

80 8281

8384(+minus)-Goniomitine (1)

Scheme 11 Reagents and conditions (a) (i) n-BuLi (22 equiv) THF (0∘C 30min) (ii) EtI (15 equiv) 0∘C (20min) (iii) benzyl chloroformate(105 equiv) 0∘C (20min) (b) (i) NaBH

4

(105 equiv) MeOH (0∘C 15min) (ii) conc H2

SO4

Et2

O (rt 1 h) (c) N2

CH2

COOEt (40 equiv)(CuOTf)

2

sdotC7

H8

(002 equiv) CH2

Cl2

(18 h) (d) (i) BF3

sdotOEt2

(015 equiv) CH2

Cl2

(minus20 to 0∘C) (ii) NaOH (90 equiv) H2

O-THF-EtOH(1 1 3) 0∘C to 60∘C (2 h) (e) (i) DMTMM (15 equiv) THF (rt 60min) (ii) MeNHOMeHCl (10 equiv) NMM (20 equiv) rt (36 h) (f)TIPSCl (105 equiv) imidazole (21 equiv) DMF (rt 1 h) (g) (i) n-BuLi (12 equiv) Et

2

O (0∘C then reflux 2 h) (ii) CO2

(0∘C 30min) (iii)H3

O+ (pH 2) (h) (i) t-BuLi (30 equiv) compound 82 (15 equiv) TMEDA (20 equiv) THF (minus78∘C 3 h) (ii) amide 79 (10 equiv) THF (0∘C20min) (i) TsOH (02 equiv) CH

2

Cl2

(rt 10min) (j) (i) NaBH4

MeOH (0∘C to rt 3 h) (ii) Ac2

O Py (rt overnight) (iii) H2

Pd-C (01equiv) EtOH (iv) TBAF (44 equiv) THF (rt 30min)

(i) a novel palladium-catalyzed decarboxylative couplingreaction between the potassium nitrophenyl acetate 118and the vinyl triflate 115 for a rapid production of thefunctionalized cyclopentene 119 (ii) a late-stage construc-tion of the whole tetracyclic scaffold of goniomitine (1)from the functionalized cyclopentene 120 by a one-potintegrated oxidationreductioncyclization (IORC) sequence(Scheme 16)

5 Conclusions

In summary it may be concluded that this brief surveyon the chemistry of goniomitine has covered the literaturerelative to this alkaloid and analogs from 1987 to the firstsemester of the year 2013 Taking into account the resultspublished in this period a considerable progress on thesynthesis of this alkaloid has been verified in the last years(2008ndash2013) with the publications of five racemic and twoenantiomeric syntheses It is also important to emphasize therecent pioneering works on the bioactive assays performedwith the racemic mixtures as well as both enantiomers ofgoniomitine In spite of these progresses the development

of new efficient enantioselective synthetic strategies for thisindole alkaloid with low operational costs is still a target tobe reached

Abbreviations

Ac Acetyl9-BBN 9-Borabicyclo[331] nonaneBoc tert-ButoxycarbonylBn Benzyln-Bu n-Butylt-Bu tert-ButylBz BenzoylDIAD Diisopropyl azodicarboxylateDIBAL Diisobutylaluminum hydrideDMF NN-DimethylformamideDMSO Dimethyl sulfoxideDMTMM 24-Dimethoxy-6-(4-methylmorpholin-4-

ium-4-yl) chlorideDPPA Diphenylphosphoryl azide


H

O

N

O

N

O

NH

N

O

NH

N

O

N

N

NH

R

N

NH

H

a

b

c

d

e

fg

i

h

j

TBDPSO TBDPSO

TBDPSO

+ OBn

OBn

OBn(84)

OR

(97) 87 R = H88 R = Ms

(80)

(80)

OTBDPSOTBDPSOTBDPS

OTBDPS

Boc

HO

Bn

BnBnBn

(58)

+(42)(97)

(87)

(48) 94 R = Bn95 R = H

(100)

OH


85 8689

90

67

919293

n-Bu3Sn

Scheme 12 Reagents and conditions (a) (i) compound 85 (13 equiv) n-BuLi (12 equiv) THF (minus78∘C 15 h) (ii) compound 86 (10 equiv)THF (rt 22 h) (b) MsCl (16 equiv) Et

3

N (20 equiv) CH2

Cl2

(0∘C to rt 20min) (c) (i) LDA (24 equiv) n-Bu3

SnH (24 equiv) THF(minus78∘C 1 h) (ii) CuBrsdotSMe

2

(27 equiv) minus78∘C (40min) (iii) mesylate 88 (10 equiv) THF (minus78∘C 1 h) (d) (i) 2-I-PhNHBoc (128 equiv)compound 89 (10 equiv) TBAC (329 equiv) TFP (025 equiv) Pd

2

(dba)3

(003 equiv) CuI (011 equiv) DMF (rt 2 h) (e) (i) o-NO2

PhSeCN(154 equiv) n-Bu

3

P (155 equiv) THF (rt 5 h) (ii) 30 aq H2

O2

(148mol Lminus1) THF (0∘C (20min) rt (17 h)) (f) compound 90 (10 equiv)lactam 91 (944 equiv) Hoveyda-Grubbs-II cat (03 equiv) neat (140∘C 3 h) (g) H

2

5 Pd-C (01 equiv) AcOEt (rt 23 h) (h) DIBAL (34equiv) THF (minus78∘C to rt) (i) H

2

20 Pd (OH)2

AcOH-EtOH (5 2) rt (2 h) (j) TBAF (33 equiv) THF (rt 14 h)

Et EthylHMPA HexamethylphosphoramideLDA Lithium diisopropylamideLiHMDS Lithium bis(trimethylsilyl)amidem-CPBA meta-Chloroperbenzoic acidMe MethylMs Mesyl (methanesulfonyl)NMM N-methylmorpholinePd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)

i-Pr iso-Propyln-Pr n-PropylPh PhenylPy PyridineTBAC Tetrabutylammonium chlorideTBAF Tetrabutylammonium fluoride

TBDPS tert-ButyldiphenylsilylTBS tert-ButyldimethylsilylTf TrifluoromethanesulfonylTFA Trifluoroacetic acidTFP TetrafluorophenylTHF TetrahydrofuranTHP TetrahydropyranylTIPSCl Triisopropylsilyl chloride (chlorotriisopro-

pylsilane)TMEDA 1198731198731198731015840 1198731015840-TetramethylethylenediamineTMSCl TrimethylsilylchlorideTMSOTf Trimethylsilyl trifluoromethanesulfonateTs Tosyl (119901-toluenesulfonyl)X-Phos 2-Dicyclohexylphosphino-210158404101584061015840-

triisopropylbiphenyl


N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)

(minus)-Goniomitine (1)

CH2

CH2

Scheme 13 Reagents and conditions (a) (i) O3

MeOH (minus78∘C 15min) and (ii) NaBH4

(15 equiv) minus78∘C to rt (2 h) (b) (i) o-NO2


3

P (60 equiv) THF (rt 3 h) and (ii) 30 aq H2

O2

THF (0∘C to rt 9 h) (c) indole 90 (10 equiv) lactam 97 (35 equiv)Hoveyda-Grubbs-II cat (031 equiv) xylene (140∘C 3 h) (d) H

2

5 Pd-C (01 equiv) AcOEt (rt 27 h) (e) (i) NaH (178 equiv) Et2

O (0∘C30min) and (ii) DIBAL (107 equiv) 0∘C to rt (10min) repeat three-times (f) H

2

20 Pd (OH)2

n-PrOH14-dioxane (1 1) rt (11 h) (g)TBAF (33 equiv) THF (rt 14 h)

N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)


Scheme 14 Reagents and conditions (a) (i) NaI (15 equiv) TMSCl (15 equiv) MeCN (rt 30min) (ii) lactone 101 (10 equiv) MeCN (rt16 h) (iii) TMSCl (05 equiv) EtOH (rt 71 h) (b) compound 102 (10 equiv) norbornene (201 equiv) K

2

CO3

(401 equiv) iodide 103 (401equiv) PdCl

2

(01 equiv) DMF-DMSO (9 1) H2

O (05mol Lminus1) air (60∘C 26 h) (c) (i) indole 104 (10 equiv) LiHMDS (30 equiv) THF(minus78∘C to rt) (ii) CH

2

=CHCH2

Br (30 equiv) (minus78∘C (40min) rt (30min)) (d) (i) lactam 105 (10 equiv) 9-BBN (139 equiv) (0∘C (15min)rt (1 h)) (ii) aq NaOH (1mol Lminus1) 35 aq H

2

O2

(018mol Lminus1) 0∘C (30min) (e) alcohol 106 (10 equiv) PPh3

(208 equiv) DPPA (294equiv) DIAD (28 equiv) 0∘C to rt (35 h) (f) azide 107 (10 equiv) LiAlH

4

(401 equiv) THF (0∘C to rt 2 h) (g) AcOH-THF-H2

O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me

(minus)-Vincadifformine (2)

5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)


CN (573 equiv) AcOH (rt 25 h) (b) TiCl3

(31 equiv) MeOH(rt 20 h) (c) compound 109 (10 equiv) HCO

2

NH4

(571 equiv) 10 Pd-C (033 equiv) MeOH (reflux 45min) (d) 4mol Lminus1 HCl (100∘C1 h)

Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)

Scheme 16 Reagents and conditions (a) (i) compound 113 (20 equiv) CH3

MgCl (20 equiv) THF (minus78∘C to rt) (ii) Mg (22 equiv) reflux(3 h) (iii) compound 112 (10 equiv) THF (reflux 2 h) (iv) 2mol Lminus1HCl (0∘C 3 h) (b) TBSCl (11 equiv) imidazole (15 equiv) DMF (rt 3 h)(c) (i) CuBrsdotMe

2

S (20 equiv) EtMgBr (40 equiv) THF (minus78 tominus40∘C 40min) (ii) compound 114 (10 equiv) THF (minus40∘C 3 h) (iii) Cominsrsquoreagent (20 equiv) THF (rt 24 h) (d) compound 116 (10 equiv) ICH

2

CH2

OBn (12 equiv) Cs2

CO3

(13 equiv) DMF (60∘C overnight)(e) compound 117 (10 equiv) 10 aq KOH MeOH-THF (5 1) rt (5-6 h) (f) t-BuOK (10 equiv) EtOH (rt 1 h) (g) (i) compound 118(12 equiv) [PdCl(allyl)]

2

(5mol) X-Phos (15mol) triflate 115 (10 equiv) diglyme (100∘C 2 h) (ii) TBAF (40 equiv) THF (rt 4 h) (h)compound 119 (10 equiv) Ph

3

P (21 equiv) DPPA (29 equiv) DIAD (28 equiv) THF (0∘C to rt 35 h) (i) (i) compound 120 (10 equiv)NaHCO

3

(50 equiv) MeOH O3

(minus78∘C 20ndash30 seg) (ii) Me2

S (50 equiv) minus78∘C to rt (24 h) (iii) Zn (70 equiv) CaCl2

(20 equiv) MeOH(reflux 2 h) (j) compound 121 (10 equiv) sodium naphthalenide (60 equiv) THF (minus20∘C 15min)


References

[1] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997

[2] M El-Sayed and R Verpoorte ldquoCatharanthus terpenoid indolealkaloids biosynthesis and regulationrdquo Phytochemistry Reviewsvol 6 no 2-3 pp 277ndash305 2007

[3] M Frederich M Tits and L Angenot ldquoPotential antimalarialactivity of indole alkaloidsrdquo Transactions of the Royal Society ofTropical Medicine and Hygiene vol 102 no 1 pp 11ndash19 2008

[4] J Ziegler and P J Facchini ldquoAlkaloid biosynthesis metabolismand traffickingrdquoAnnual Review of Plant Biology vol 59 pp 735ndash769 2008

[5] J Hajıcek ldquoRecent developments in syntheses of the post-secodine indole alkaloids Part III rearranged alkaloid typesrdquoCollection of Czechoslovak Chemical Communications vol 76no 12 pp 2023ndash2083 2011

[6] L Randriambola J-C Quirion C Kan-Fan and H-P HussonldquoStructure of goniomitine a new type of indole alkaloidrdquoTetrahedron Letters vol 28 no 19 pp 2123ndash2126 1987

[7] C Hashimoto and H-P Husson ldquoSynthetic and structuralstudies in the goniomitine alkaloid series a new reductivecyclization reaction in the indole fieldrdquo Tetrahedron Letters vol29 no 36 pp 4563ndash4566 1988

[8] S Takano T Sato K Inomata and K Ogasawara ldquoTheenantiocontrolled total synthesis of natural (-)-goniomitinerdquoJournal of the Chemical Society Chemical Communications no7 pp 462ndash464 1991

[9] G Lewin C Schaeffer and P H Lambert ldquoNew rearrangementof an Aspidosperma alkaloid the first biomimetic entry in thegoniomitine skeletonrdquo The Journal of Organic Chemistry vol60 no 11 pp 3282ndash3287 1995

[10] G Lewin and C Schaeffer ldquoSemisynthesis of (+)-(16S20S 21R)-16-hydroxymethyl-goniomitine from (minus) vincad-ifforminerdquo Natural Product Letters vol 7 no 3 pp 227ndash2341995

[11] C F Gurtler E Steckhan and S Blechert ldquo[4 + 2]-cycloaddition reactions between 120573-acceptor-substituted enam-ines and 2-vinylindole radical cations acting as hetero-dienesrdquoThe Journal of Organic Chemistry vol 61 no 12 pp 4136ndash41431996

[12] J C F Alves Proposal of enantioselective synthesis of the indolealkaloid (-)-goniomitine and stereoisomers [Qualification Examof Doctorate] NPPN Universidade Federal do Rio de JaneiroRio de Janeiro Brazil 2000

[13] G Lewin C Schaeffer R Hocquemiller et al ldquoAccess to newcytotoxic bisindole alkaloids by a modified Borch reductiveamination processrdquo Heterocycles vol 53 no 11 pp 2353ndash23562000

[14] R F Borch M D Bernstein and H D Durst ldquoThe cyanohy-dridoborate anion as a selective reducing agentrdquo Journal of theAmerican Chemical Society vol 93 no 12 pp 2897ndash2904 1971

[15] G Lewin and C Schaeffer ldquoOne-pot access to 23-disubstituted1234-tetrahydroquinolines by reductive amination of aldehy-des with sodium cyanoborohydriderdquoHeterocycles vol 48 no 1pp 171ndash174 1998

[16] M Raoul C Schaeffer S Leonce et al ldquoSynthesis of a novelseries of cytotoxic bisindole alkaloidsrdquo Bioorganic amp MedicinalChemistry Letters vol 11 no 1 pp 79ndash81 2001

[17] C L Morales and B L Pagenkopf ldquoTotal synthesis of (plusmn)-goniomitine via a formal nitriledonor-acceptor cyclopropane

[3 + 2] cyclizationrdquo Organic Letters vol 10 no 2 pp 157ndash1592008

[18] F de Simone J Gertsch and J Waser ldquoCatalytic selectivecyclizations of aminocyclopropanes formal synthesis of aspi-dospermidine and total synthesis of goniomitinerdquo AngewandteChemie International Edition vol 49 no 33 pp 5767ndash57702010

[19] F De Simone J Gertsch and J Waser ldquoCorrigendum catalyticselective cyclizations of aminocyclopropanes formal synthesisof aspidospermidine and total synthesis of goniomitinerdquo Ange-wandte Chemie International Edition vol 50 no 18 p 40382011

[20] F De Simone and J Waser ldquoCyclization of aminocyclo-propanes in indole alkaloids synthesisrdquo Synlett no 5 Article IDP00710ST pp 589ndash593 2011

[21] M Mizutani F Inagaki T Nakanishi C Yanagihara I Tamaiand C Mukai ldquoTotal syntheses of (minus)- and (+)-goniomitinerdquoOrganic Letters vol 13 no 7 pp 1796ndash1799 2011

[22] C Mukai and Y Takahashi ldquoA new entry to the synthesis of 23-disubstituted indolesrdquo Organic Letters vol 7 no 26 pp 5793ndash5796 2005

[23] L Jiao E Herdtweck and T Bach ldquoPd(II)-catalysed regios-elective 2-alkylation of indoles via a norbornene-mediatedC-H activation mechanism and applicationsrdquo Journal of theAmerican Chemical Society vol 134 no 35 pp 14563ndash145722012

[24] L Jiao and T Bach ldquoPalladium-catalyzed direct 2-alkylationof indoles by norbornene-mediated regioselective cascade C-Hactivationrdquo Journal of the American Chemical Society vol 133no 33 pp 12990ndash12993 2011

[25] G Lewin G Bernadat G Aubert and T Cresteil ldquoSemisyn-thesis of (+)- and (minus)-goniomitine from (minus)- and (+)-vincadifforminerdquoTetrahedron vol 69 no 5 pp 1622ndash1627 2013

[26] Z Xu Q Wang and J Zhu ldquoPalladium-catalyzed decarboxyla-tive vinylation of potassium nitrophenyl acetate application tothe total synthesis of (+minus)-goniomitinerdquo Angewandte ChemieInternational Edition vol 52 no 11 pp 3272ndash3276 2013

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


OH

N

N

H

H

S21

R20

OH

N

N

H

H

S21R

20

(unnatural)(20S 21R)-(+)-Goniomitine (1)

(natural)(20R 21S)-(minus)-Goniomitine (1)

Figure 1 Natural (minus)- and unnatural (+)-goniomitine (1)

c

d

NH

N

H

1 2

34

56

789

10

1112

13

1415

1617 18

192021

CO2Me

a-b

N

N

H

H

HHO

+ NH

NHHO +

N

NH

H

+

OH

N

NH

H

12

34

56

78910

1112

13

14

15

16

17 181920

21

OH

1

2 3 44

Scheme 1 Biogenetic hypothesis of transformation of vincadifformine (2) into goniomitine (1) (a) oxidative fission of the C-5 N-4 bond (b)decarboxylation (c) retro-Mannich reaction (d) nucleophilic attack of the indole nitrogen on the iminium moiety

N

NHH

OH

N

NH

OH

Ac

Ac2O Ac2OMeOH Py

N

NH

Ac

OAc

15 6

Scheme 2 Chemical transformations of goniomitine (1) into the acetyl derivatives 5 and 6


NH

N

NH

N

NH

N

NH

N

I

a b c d

e

N H

CH3

TMS

(55) (57)

OH

(97)

OH OH

(91)

Me Me

(59)

+

minus

N

NH

OH

Me

+

(36 23)

(+minus)-12

7 8 9 10 11

11


2


Cl2

(reflux 2 h) (d) H2

PtO2

MeOH (3 h) (e)H2

PtO2

NaOMe MeOH (3 h)












O

HH

O

HH O O

S

S

O

SS

O

HO

O

d

i

NH

O

I

NH

O

N

O

NH

O

N

O

NH

H

O

NH

N NH

m

t

u

21

z

y

NH

O NH

O

N

NH

O

q

l

a-c(53)

(minus)-13

e-f

g-h (75)

MeOMeOMeO j-k

OEt

OEt

(81)

CO2Me

(81)

OMe

(11 70)

+

n-p

NH2

HN

HN

HNHN

HN HN HN

r-s

CN

CN CN

Cl minus +

v-x

OH

(82)31 C21-H120573

(minus)-1 C21-H120572

15 16

171819

21 2322

24

28 29 30

27 26 25

14

20

(82 rArr 17)

(78 rArr 25) (65 rArr 23)

(84 rArr 27) (40 rArr 29)

(72 rArr 14)


4


2

N2

Et2



3

P (40 equiv) CBr4

(20 equiv) Et3

N (30 equiv) CH2

Cl2


2

(PPh3

)2

(2) CuI (5) Et3



2

O2


P (13 equiv)(i-PrO

2

CN)2


NH2

sdotH2


N=CH2

]Cl (15 equiv) CH2

Cl2


3



2

Cl2


SO4

(y) NaBH4



N

N

H

OO

O

N

N

H

OO

O

N

N

H

N

N

H

O

N

N

Cl Cl Cl

ClCl

H

N

NH

O

NH

N

H

OO

O

N

N

H

O

N

NH

NH

N

H

5 5

55b

a

5

c

5

d

e

f

g

h


CO2MeCO2Me

CO2MeCO2Me

CO2Me

3 steps

MeO

(82)

+ Ar

Ar

Ar

Ar = m-Cl-C6H4

(71)

12057235a C5-H12057335b C5-H (3 1)

(100)

(18)

HO

HO

HO

(53)

CHOCHO

+

(42 11)

(40)

(52)

(48)

2 32 33 34

36

37

38

40 39


Cl2


2

Cl2


Cl2


Cl2

(rt 45 h)








N

N

Cl

O

H TFA

TFA

N

N

Cl Cl

ClHO

OHCH

N

NH

O

N

NOOHC

H

N

NH

O

CHO

CHOCHOCHO

CHO CHO CHO

N

N

H

O

H

N

NH

N

NO

N

NH

O

H N

NH

a

b

b

a

HO

HO HO

CO2Me CO2Me CO2Me

CO2Me

CO2MeCO2MeCO2Me

CO2Me CO2Me CO2Me

CH2Cl2

+

+

minus

minus

+minus

+

minus

+

minus

OCOCF3

36

39

36a 36b 36b

36c36d

39a 39b 40

Scheme 6

N

NH

HO

HO

HO

HO

HO

CHO

N

NH

N

NH

H

N

NH

N

NH

N

NH

H

H N

NH

H

a b

c

d e f

CO2Me CO2Me

(62)

OH OH

OHOHOHOH

OH OH OH

(43)

CO2H

CH3

(75)(66)(35)

(57)

40 41 42

43 44 45 46




2


-H2



N

NH

CN

CNMe

H

OEt

N

NHH

N

Me

Me

NH

CN

HNH

CN

N

Me

Me

Me

Me

Me N

CN

CN

CN

H

a

b

c

d

N

CO2Me

R2

R1 R3

(62)

+(68)


(53)

(91)

47 R1 = Me48 R1 = (CH2)2OEt

CO2Me

55

52

53

54


CN LiClO4


3


CN LiClO4


3


CNLiClO

4



3

CN LiClO4









N

NH

AcO

HN

HN

HN

HN

HN

NNH

AcO

N

NH

N

NH

NNH

N

NH

H

NNH

H

N

NH

N

NNH

Ac

Ac

Ac

Ac

Ac

N

NH

NN

N

NH

HO

HN

NNH

HO

OH

OH

N

NH

CHO

N

NH

HO

N

NNH

HO

HO

HOHOHO

Me

ab

c

d

ef

g

MeO2C

MeO2C

MeO2C

MeO2CMeO2C

CO2Me CO2Me

CO2Me

CO2Me

CO2MeCO2Me

CO2MeCO2Me

(64)

MeO2C

(68)

Ph

+

+

+

(23 28)

(51)(45)

(38)(70

)

(48 22)

(32)

40 56 57

58

58

59

6061

6263

64

NH2 middot HCl



3


-H2




O NaBH3


THF (reflux 3 h)


N

O

NH

NH

O

NH

NH

OCN

N

CN

HN HN HN

H

N

OBn

Bn

BnBn

X

NH

NH

N

O

NH

N

OBn

CN

OMe

NH

NH

N

O

NH

N

O

a

f

g

hi

j j

i

k

l m

2021 21 21

20 20

R 2R1

b c(828)

(83) 65 R1 = R2 = H66 R1 = Et R2 = Bn

+

d e(70) 67 X = OH

68 X = CN

CO2Et

CO2Et

CO2Et

(74)

(98)

(75)(97)

(trace)

(97)

(70)

(70)

(44)

OH OH

(79)


69 70

717225

27 73

29 31


2

CH2


3


Cl2


2


2



2

N=CH2

]Cl (15 equiv) CH2

Cl2


3



Cl2


2

SO4

(iii) NaBH4








N OH

N O N N O N OH N

N

OH

NH

NH

N

NH

O

NH

N

NH

O

N

NH

H

a b c d e

hf g

ij

(67)

Cbz Cbz Cbz Cbz

CbzCbz

Cbz

(93) (76)OEt

(91)OH

OH

OH

(93) OMe

Me

(48)

OTIPSOTIPS

OTIPS OTIPS

COOH

(100)

(77) (93)

H+

74 75 76 77 78 79

80 8281



4


SO4

Et2

O (rt 1 h) (c) N2

CH2


2

sdotC7

H8

(002 equiv) CH2

Cl2

(18 h) (d) (i) BF3

sdotOEt2

(015 equiv) CH2

Cl2



2




2

Cl2






5 Conclusions



Abbreviations




H

O

N

O

N

O

NH

N

O

NH

N

O

N

N

NH

R

N

NH

H

a

b

c

d

e

fg

i

h

j

TBDPSO TBDPSO

TBDPSO

+ OBn

OBn

OBn(84)

OR

(97) 87 R = H88 R = Ms

(80)

(80)

OTBDPSOTBDPSOTBDPS

OTBDPS

Boc

HO

Bn

BnBnBn

(58)

+(42)(97)

(87)

(48) 94 R = Bn95 R = H

(100)

OH


85 8689

90

67

919293

n-Bu3Sn


3

N (20 equiv) CH2

Cl2



2


2

(dba)3



3


O2


2


2

20 Pd (OH)2








N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)


CH2

CH2





3


O2


2



2

20 Pd (OH)2


N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)



2

CO3


2



2

=CHCH2


2

O2



4


O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


NH

N

NH

N

NH

N

NH

N

I

a b c d

e

N H

CH3

TMS

(55) (57)

OH

(97)

OH OH

(91)

Me Me

(59)

+

minus

N

NH

OH

Me

+

(36 23)

(+minus)-12

7 8 9 10 11

11


2


Cl2

(reflux 2 h) (d) H2

PtO2

MeOH (3 h) (e)H2

PtO2

NaOMe MeOH (3 h)












O

HH

O

HH O O

S

S

O

SS

O

HO

O

d

i

NH

O

I

NH

O

N

O

NH

O

N

O

NH

H

O

NH

N NH

m

t

u

21

z

y

NH

O NH

O

N

NH

O

q

l

a-c(53)

(minus)-13

e-f

g-h (75)

MeOMeOMeO j-k

OEt

OEt

(81)

CO2Me

(81)

OMe

(11 70)

+

n-p

NH2

HN

HN

HNHN

HN HN HN

r-s

CN

CN CN

Cl minus +

v-x

OH

(82)31 C21-H120573

(minus)-1 C21-H120572

15 16

171819

21 2322

24

28 29 30

27 26 25

14

20

(82 rArr 17)

(78 rArr 25) (65 rArr 23)

(84 rArr 27) (40 rArr 29)

(72 rArr 14)


4


2

N2

Et2



3

P (40 equiv) CBr4

(20 equiv) Et3

N (30 equiv) CH2

Cl2


2

(PPh3

)2

(2) CuI (5) Et3



2

O2


P (13 equiv)(i-PrO

2

CN)2


NH2

sdotH2


N=CH2

]Cl (15 equiv) CH2

Cl2


3



2

Cl2


SO4

(y) NaBH4



N

N

H

OO

O

N

N

H

OO

O

N

N

H

N

N

H

O

N

N

Cl Cl Cl

ClCl

H

N

NH

O

NH

N

H

OO

O

N

N

H

O

N

NH

NH

N

H

5 5

55b

a

5

c

5

d

e

f

g

h


CO2MeCO2Me

CO2MeCO2Me

CO2Me

3 steps

MeO

(82)

+ Ar

Ar

Ar

Ar = m-Cl-C6H4

(71)

12057235a C5-H12057335b C5-H (3 1)

(100)

(18)

HO

HO

HO

(53)

CHOCHO

+

(42 11)

(40)

(52)

(48)

2 32 33 34

36

37

38

40 39


Cl2


2

Cl2


Cl2


Cl2

(rt 45 h)








N

N

Cl

O

H TFA

TFA

N

N

Cl Cl

ClHO

OHCH

N

NH

O

N

NOOHC

H

N

NH

O

CHO

CHOCHOCHO

CHO CHO CHO

N

N

H

O

H

N

NH

N

NO

N

NH

O

H N

NH

a

b

b

a

HO

HO HO

CO2Me CO2Me CO2Me

CO2Me

CO2MeCO2MeCO2Me

CO2Me CO2Me CO2Me

CH2Cl2

+

+

minus

minus

+minus

+

minus

+

minus

OCOCF3

36

39

36a 36b 36b

36c36d

39a 39b 40

Scheme 6

N

NH

HO

HO

HO

HO

HO

CHO

N

NH

N

NH

H

N

NH

N

NH

N

NH

H

H N

NH

H

a b

c

d e f

CO2Me CO2Me

(62)

OH OH

OHOHOHOH

OH OH OH

(43)

CO2H

CH3

(75)(66)(35)

(57)

40 41 42

43 44 45 46




2


-H2



N

NH

CN

CNMe

H

OEt

N

NHH

N

Me

Me

NH

CN

HNH

CN

N

Me

Me

Me

Me

Me N

CN

CN

CN

H

a

b

c

d

N

CO2Me

R2

R1 R3

(62)

+(68)


(53)

(91)

47 R1 = Me48 R1 = (CH2)2OEt

CO2Me

55

52

53

54


CN LiClO4


3


CN LiClO4


3


CNLiClO

4



3

CN LiClO4









N

NH

AcO

HN

HN

HN

HN

HN

NNH

AcO

N

NH

N

NH

NNH

N

NH

H

NNH

H

N

NH

N

NNH

Ac

Ac

Ac

Ac

Ac

N

NH

NN

N

NH

HO

HN

NNH

HO

OH

OH

N

NH

CHO

N

NH

HO

N

NNH

HO

HO

HOHOHO

Me

ab

c

d

ef

g

MeO2C

MeO2C

MeO2C

MeO2CMeO2C

CO2Me CO2Me

CO2Me

CO2Me

CO2MeCO2Me

CO2MeCO2Me

(64)

MeO2C

(68)

Ph

+

+

+

(23 28)

(51)(45)

(38)(70

)

(48 22)

(32)

40 56 57

58

58

59

6061

6263

64

NH2 middot HCl



3


-H2




O NaBH3


THF (reflux 3 h)


N

O

NH

NH

O

NH

NH

OCN

N

CN

HN HN HN

H

N

OBn

Bn

BnBn

X

NH

NH

N

O

NH

N

OBn

CN

OMe

NH

NH

N

O

NH

N

O

a

f

g

hi

j j

i

k

l m

2021 21 21

20 20

R 2R1

b c(828)

(83) 65 R1 = R2 = H66 R1 = Et R2 = Bn

+

d e(70) 67 X = OH

68 X = CN

CO2Et

CO2Et

CO2Et

(74)

(98)

(75)(97)

(trace)

(97)

(70)

(70)

(44)

OH OH

(79)


69 70

717225

27 73

29 31


2

CH2


3


Cl2


2


2



2

N=CH2

]Cl (15 equiv) CH2

Cl2


3



Cl2


2

SO4

(iii) NaBH4








N OH

N O N N O N OH N

N

OH

NH

NH

N

NH

O

NH

N

NH

O

N

NH

H

a b c d e

hf g

ij

(67)

Cbz Cbz Cbz Cbz

CbzCbz

Cbz

(93) (76)OEt

(91)OH

OH

OH

(93) OMe

Me

(48)

OTIPSOTIPS

OTIPS OTIPS

COOH

(100)

(77) (93)

H+

74 75 76 77 78 79

80 8281



4


SO4

Et2

O (rt 1 h) (c) N2

CH2


2

sdotC7

H8

(002 equiv) CH2

Cl2

(18 h) (d) (i) BF3

sdotOEt2

(015 equiv) CH2

Cl2



2




2

Cl2






5 Conclusions



Abbreviations




H

O

N

O

N

O

NH

N

O

NH

N

O

N

N

NH

R

N

NH

H

a

b

c

d

e

fg

i

h

j

TBDPSO TBDPSO

TBDPSO

+ OBn

OBn

OBn(84)

OR

(97) 87 R = H88 R = Ms

(80)

(80)

OTBDPSOTBDPSOTBDPS

OTBDPS

Boc

HO

Bn

BnBnBn

(58)

+(42)(97)

(87)

(48) 94 R = Bn95 R = H

(100)

OH


85 8689

90

67

919293

n-Bu3Sn


3

N (20 equiv) CH2

Cl2



2


2

(dba)3



3


O2


2


2

20 Pd (OH)2








N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)


CH2

CH2





3


O2


2



2

20 Pd (OH)2


N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)



2

CO3


2



2

=CHCH2


2

O2



4


O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O

HH

O

HH O O

S

S

O

SS

O

HO

O

d

i

NH

O

I

NH

O

N

O

NH

O

N

O

NH

H

O

NH

N NH

m

t

u

21

z

y

NH

O NH

O

N

NH

O

q

l

a-c(53)

(minus)-13

e-f

g-h (75)

MeOMeOMeO j-k

OEt

OEt

(81)

CO2Me

(81)

OMe

(11 70)

+

n-p

NH2

HN

HN

HNHN

HN HN HN

r-s

CN

CN CN

Cl minus +

v-x

OH

(82)31 C21-H120573

(minus)-1 C21-H120572

15 16

171819

21 2322

24

28 29 30

27 26 25

14

20

(82 rArr 17)

(78 rArr 25) (65 rArr 23)

(84 rArr 27) (40 rArr 29)

(72 rArr 14)


4


2

N2

Et2



3

P (40 equiv) CBr4

(20 equiv) Et3

N (30 equiv) CH2

Cl2


2

(PPh3

)2

(2) CuI (5) Et3



2

O2


P (13 equiv)(i-PrO

2

CN)2


NH2

sdotH2


N=CH2

]Cl (15 equiv) CH2

Cl2


3



2

Cl2


SO4

(y) NaBH4



N

N

H

OO

O

N

N

H

OO

O

N

N

H

N

N

H

O

N

N

Cl Cl Cl

ClCl

H

N

NH

O

NH

N

H

OO

O

N

N

H

O

N

NH

NH

N

H

5 5

55b

a

5

c

5

d

e

f

g

h


CO2MeCO2Me

CO2MeCO2Me

CO2Me

3 steps

MeO

(82)

+ Ar

Ar

Ar

Ar = m-Cl-C6H4

(71)

12057235a C5-H12057335b C5-H (3 1)

(100)

(18)

HO

HO

HO

(53)

CHOCHO

+

(42 11)

(40)

(52)

(48)

2 32 33 34

36

37

38

40 39


Cl2


2

Cl2


Cl2


Cl2

(rt 45 h)








N

N

Cl

O

H TFA

TFA

N

N

Cl Cl

ClHO

OHCH

N

NH

O

N

NOOHC

H

N

NH

O

CHO

CHOCHOCHO

CHO CHO CHO

N

N

H

O

H

N

NH

N

NO

N

NH

O

H N

NH

a

b

b

a

HO

HO HO

CO2Me CO2Me CO2Me

CO2Me

CO2MeCO2MeCO2Me

CO2Me CO2Me CO2Me

CH2Cl2

+

+

minus

minus

+minus

+

minus

+

minus

OCOCF3

36

39

36a 36b 36b

36c36d

39a 39b 40

Scheme 6

N

NH

HO

HO

HO

HO

HO

CHO

N

NH

N

NH

H

N

NH

N

NH

N

NH

H

H N

NH

H

a b

c

d e f

CO2Me CO2Me

(62)

OH OH

OHOHOHOH

OH OH OH

(43)

CO2H

CH3

(75)(66)(35)

(57)

40 41 42

43 44 45 46




2


-H2



N

NH

CN

CNMe

H

OEt

N

NHH

N

Me

Me

NH

CN

HNH

CN

N

Me

Me

Me

Me

Me N

CN

CN

CN

H

a

b

c

d

N

CO2Me

R2

R1 R3

(62)

+(68)


(53)

(91)

47 R1 = Me48 R1 = (CH2)2OEt

CO2Me

55

52

53

54


CN LiClO4


3


CN LiClO4


3


CNLiClO

4



3

CN LiClO4









N

NH

AcO

HN

HN

HN

HN

HN

NNH

AcO

N

NH

N

NH

NNH

N

NH

H

NNH

H

N

NH

N

NNH

Ac

Ac

Ac

Ac

Ac

N

NH

NN

N

NH

HO

HN

NNH

HO

OH

OH

N

NH

CHO

N

NH

HO

N

NNH

HO

HO

HOHOHO

Me

ab

c

d

ef

g

MeO2C

MeO2C

MeO2C

MeO2CMeO2C

CO2Me CO2Me

CO2Me

CO2Me

CO2MeCO2Me

CO2MeCO2Me

(64)

MeO2C

(68)

Ph

+

+

+

(23 28)

(51)(45)

(38)(70

)

(48 22)

(32)

40 56 57

58

58

59

6061

6263

64

NH2 middot HCl



3


-H2




O NaBH3


THF (reflux 3 h)


N

O

NH

NH

O

NH

NH

OCN

N

CN

HN HN HN

H

N

OBn

Bn

BnBn

X

NH

NH

N

O

NH

N

OBn

CN

OMe

NH

NH

N

O

NH

N

O

a

f

g

hi

j j

i

k

l m

2021 21 21

20 20

R 2R1

b c(828)

(83) 65 R1 = R2 = H66 R1 = Et R2 = Bn

+

d e(70) 67 X = OH

68 X = CN

CO2Et

CO2Et

CO2Et

(74)

(98)

(75)(97)

(trace)

(97)

(70)

(70)

(44)

OH OH

(79)


69 70

717225

27 73

29 31


2

CH2


3


Cl2


2


2



2

N=CH2

]Cl (15 equiv) CH2

Cl2


3



Cl2


2

SO4

(iii) NaBH4








N OH

N O N N O N OH N

N

OH

NH

NH

N

NH

O

NH

N

NH

O

N

NH

H

a b c d e

hf g

ij

(67)

Cbz Cbz Cbz Cbz

CbzCbz

Cbz

(93) (76)OEt

(91)OH

OH

OH

(93) OMe

Me

(48)

OTIPSOTIPS

OTIPS OTIPS

COOH

(100)

(77) (93)

H+

74 75 76 77 78 79

80 8281



4


SO4

Et2

O (rt 1 h) (c) N2

CH2


2

sdotC7

H8

(002 equiv) CH2

Cl2

(18 h) (d) (i) BF3

sdotOEt2

(015 equiv) CH2

Cl2



2




2

Cl2






5 Conclusions



Abbreviations




H

O

N

O

N

O

NH

N

O

NH

N

O

N

N

NH

R

N

NH

H

a

b

c

d

e

fg

i

h

j

TBDPSO TBDPSO

TBDPSO

+ OBn

OBn

OBn(84)

OR

(97) 87 R = H88 R = Ms

(80)

(80)

OTBDPSOTBDPSOTBDPS

OTBDPS

Boc

HO

Bn

BnBnBn

(58)

+(42)(97)

(87)

(48) 94 R = Bn95 R = H

(100)

OH


85 8689

90

67

919293

n-Bu3Sn


3

N (20 equiv) CH2

Cl2



2


2

(dba)3



3


O2


2


2

20 Pd (OH)2








N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)


CH2

CH2





3


O2


2



2

20 Pd (OH)2


N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)



2

CO3


2



2

=CHCH2


2

O2



4


O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

N

H

OO

O

N

N

H

OO

O

N

N

H

N

N

H

O

N

N

Cl Cl Cl

ClCl

H

N

NH

O

NH

N

H

OO

O

N

N

H

O

N

NH

NH

N

H

5 5

55b

a

5

c

5

d

e

f

g

h


CO2MeCO2Me

CO2MeCO2Me

CO2Me

3 steps

MeO

(82)

+ Ar

Ar

Ar

Ar = m-Cl-C6H4

(71)

12057235a C5-H12057335b C5-H (3 1)

(100)

(18)

HO

HO

HO

(53)

CHOCHO

+

(42 11)

(40)

(52)

(48)

2 32 33 34

36

37

38

40 39


Cl2


2

Cl2


Cl2


Cl2

(rt 45 h)








N

N

Cl

O

H TFA

TFA

N

N

Cl Cl

ClHO

OHCH

N

NH

O

N

NOOHC

H

N

NH

O

CHO

CHOCHOCHO

CHO CHO CHO

N

N

H

O

H

N

NH

N

NO

N

NH

O

H N

NH

a

b

b

a

HO

HO HO

CO2Me CO2Me CO2Me

CO2Me

CO2MeCO2MeCO2Me

CO2Me CO2Me CO2Me

CH2Cl2

+

+

minus

minus

+minus

+

minus

+

minus

OCOCF3

36

39

36a 36b 36b

36c36d

39a 39b 40

Scheme 6

N

NH

HO

HO

HO

HO

HO

CHO

N

NH

N

NH

H

N

NH

N

NH

N

NH

H

H N

NH

H

a b

c

d e f

CO2Me CO2Me

(62)

OH OH

OHOHOHOH

OH OH OH

(43)

CO2H

CH3

(75)(66)(35)

(57)

40 41 42

43 44 45 46




2


-H2



N

NH

CN

CNMe

H

OEt

N

NHH

N

Me

Me

NH

CN

HNH

CN

N

Me

Me

Me

Me

Me N

CN

CN

CN

H

a

b

c

d

N

CO2Me

R2

R1 R3

(62)

+(68)


(53)

(91)

47 R1 = Me48 R1 = (CH2)2OEt

CO2Me

55

52

53

54


CN LiClO4


3


CN LiClO4


3


CNLiClO

4



3

CN LiClO4









N

NH

AcO

HN

HN

HN

HN

HN

NNH

AcO

N

NH

N

NH

NNH

N

NH

H

NNH

H

N

NH

N

NNH

Ac

Ac

Ac

Ac

Ac

N

NH

NN

N

NH

HO

HN

NNH

HO

OH

OH

N

NH

CHO

N

NH

HO

N

NNH

HO

HO

HOHOHO

Me

ab

c

d

ef

g

MeO2C

MeO2C

MeO2C

MeO2CMeO2C

CO2Me CO2Me

CO2Me

CO2Me

CO2MeCO2Me

CO2MeCO2Me

(64)

MeO2C

(68)

Ph

+

+

+

(23 28)

(51)(45)

(38)(70

)

(48 22)

(32)

40 56 57

58

58

59

6061

6263

64

NH2 middot HCl



3


-H2




O NaBH3


THF (reflux 3 h)


N

O

NH

NH

O

NH

NH

OCN

N

CN

HN HN HN

H

N

OBn

Bn

BnBn

X

NH

NH

N

O

NH

N

OBn

CN

OMe

NH

NH

N

O

NH

N

O

a

f

g

hi

j j

i

k

l m

2021 21 21

20 20

R 2R1

b c(828)

(83) 65 R1 = R2 = H66 R1 = Et R2 = Bn

+

d e(70) 67 X = OH

68 X = CN

CO2Et

CO2Et

CO2Et

(74)

(98)

(75)(97)

(trace)

(97)

(70)

(70)

(44)

OH OH

(79)


69 70

717225

27 73

29 31


2

CH2


3


Cl2


2


2



2

N=CH2

]Cl (15 equiv) CH2

Cl2


3



Cl2


2

SO4

(iii) NaBH4








N OH

N O N N O N OH N

N

OH

NH

NH

N

NH

O

NH

N

NH

O

N

NH

H

a b c d e

hf g

ij

(67)

Cbz Cbz Cbz Cbz

CbzCbz

Cbz

(93) (76)OEt

(91)OH

OH

OH

(93) OMe

Me

(48)

OTIPSOTIPS

OTIPS OTIPS

COOH

(100)

(77) (93)

H+

74 75 76 77 78 79

80 8281



4


SO4

Et2

O (rt 1 h) (c) N2

CH2


2

sdotC7

H8

(002 equiv) CH2

Cl2

(18 h) (d) (i) BF3

sdotOEt2

(015 equiv) CH2

Cl2



2




2

Cl2






5 Conclusions



Abbreviations




H

O

N

O

N

O

NH

N

O

NH

N

O

N

N

NH

R

N

NH

H

a

b

c

d

e

fg

i

h

j

TBDPSO TBDPSO

TBDPSO

+ OBn

OBn

OBn(84)

OR

(97) 87 R = H88 R = Ms

(80)

(80)

OTBDPSOTBDPSOTBDPS

OTBDPS

Boc

HO

Bn

BnBnBn

(58)

+(42)(97)

(87)

(48) 94 R = Bn95 R = H

(100)

OH


85 8689

90

67

919293

n-Bu3Sn


3

N (20 equiv) CH2

Cl2



2


2

(dba)3



3


O2


2


2

20 Pd (OH)2








N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)


CH2

CH2





3


O2


2



2

20 Pd (OH)2


N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)



2

CO3


2



2

=CHCH2


2

O2



4


O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

N

Cl

O

H TFA

TFA

N

N

Cl Cl

ClHO

OHCH

N

NH

O

N

NOOHC

H

N

NH

O

CHO

CHOCHOCHO

CHO CHO CHO

N

N

H

O

H

N

NH

N

NO

N

NH

O

H N

NH

a

b

b

a

HO

HO HO

CO2Me CO2Me CO2Me

CO2Me

CO2MeCO2MeCO2Me

CO2Me CO2Me CO2Me

CH2Cl2

+

+

minus

minus

+minus

+

minus

+

minus

OCOCF3

36

39

36a 36b 36b

36c36d

39a 39b 40

Scheme 6

N

NH

HO

HO

HO

HO

HO

CHO

N

NH

N

NH

H

N

NH

N

NH

N

NH

H

H N

NH

H

a b

c

d e f

CO2Me CO2Me

(62)

OH OH

OHOHOHOH

OH OH OH

(43)

CO2H

CH3

(75)(66)(35)

(57)

40 41 42

43 44 45 46




2


-H2



N

NH

CN

CNMe

H

OEt

N

NHH

N

Me

Me

NH

CN

HNH

CN

N

Me

Me

Me

Me

Me N

CN

CN

CN

H

a

b

c

d

N

CO2Me

R2

R1 R3

(62)

+(68)


(53)

(91)

47 R1 = Me48 R1 = (CH2)2OEt

CO2Me

55

52

53

54


CN LiClO4


3


CN LiClO4


3


CNLiClO

4



3

CN LiClO4









N

NH

AcO

HN

HN

HN

HN

HN

NNH

AcO

N

NH

N

NH

NNH

N

NH

H

NNH

H

N

NH

N

NNH

Ac

Ac

Ac

Ac

Ac

N

NH

NN

N

NH

HO

HN

NNH

HO

OH

OH

N

NH

CHO

N

NH

HO

N

NNH

HO

HO

HOHOHO

Me

ab

c

d

ef

g

MeO2C

MeO2C

MeO2C

MeO2CMeO2C

CO2Me CO2Me

CO2Me

CO2Me

CO2MeCO2Me

CO2MeCO2Me

(64)

MeO2C

(68)

Ph

+

+

+

(23 28)

(51)(45)

(38)(70

)

(48 22)

(32)

40 56 57

58

58

59

6061

6263

64

NH2 middot HCl



3


-H2




O NaBH3


THF (reflux 3 h)


N

O

NH

NH

O

NH

NH

OCN

N

CN

HN HN HN

H

N

OBn

Bn

BnBn

X

NH

NH

N

O

NH

N

OBn

CN

OMe

NH

NH

N

O

NH

N

O

a

f

g

hi

j j

i

k

l m

2021 21 21

20 20

R 2R1

b c(828)

(83) 65 R1 = R2 = H66 R1 = Et R2 = Bn

+

d e(70) 67 X = OH

68 X = CN

CO2Et

CO2Et

CO2Et

(74)

(98)

(75)(97)

(trace)

(97)

(70)

(70)

(44)

OH OH

(79)


69 70

717225

27 73

29 31


2

CH2


3


Cl2


2


2



2

N=CH2

]Cl (15 equiv) CH2

Cl2


3



Cl2


2

SO4

(iii) NaBH4








N OH

N O N N O N OH N

N

OH

NH

NH

N

NH

O

NH

N

NH

O

N

NH

H

a b c d e

hf g

ij

(67)

Cbz Cbz Cbz Cbz

CbzCbz

Cbz

(93) (76)OEt

(91)OH

OH

OH

(93) OMe

Me

(48)

OTIPSOTIPS

OTIPS OTIPS

COOH

(100)

(77) (93)

H+

74 75 76 77 78 79

80 8281



4


SO4

Et2

O (rt 1 h) (c) N2

CH2


2

sdotC7

H8

(002 equiv) CH2

Cl2

(18 h) (d) (i) BF3

sdotOEt2

(015 equiv) CH2

Cl2



2




2

Cl2






5 Conclusions



Abbreviations




H

O

N

O

N

O

NH

N

O

NH

N

O

N

N

NH

R

N

NH

H

a

b

c

d

e

fg

i

h

j

TBDPSO TBDPSO

TBDPSO

+ OBn

OBn

OBn(84)

OR

(97) 87 R = H88 R = Ms

(80)

(80)

OTBDPSOTBDPSOTBDPS

OTBDPS

Boc

HO

Bn

BnBnBn

(58)

+(42)(97)

(87)

(48) 94 R = Bn95 R = H

(100)

OH


85 8689

90

67

919293

n-Bu3Sn


3

N (20 equiv) CH2

Cl2



2


2

(dba)3



3


O2


2


2

20 Pd (OH)2








N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)


CH2

CH2





3


O2


2



2

20 Pd (OH)2


N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)



2

CO3


2



2

=CHCH2


2

O2



4


O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

NH

CN

CNMe

H

OEt

N

NHH

N

Me

Me

NH

CN

HNH

CN

N

Me

Me

Me

Me

Me N

CN

CN

CN

H

a

b

c

d

N

CO2Me

R2

R1 R3

(62)

+(68)


(53)

(91)

47 R1 = Me48 R1 = (CH2)2OEt

CO2Me

55

52

53

54


CN LiClO4


3


CN LiClO4


3


CNLiClO

4



3

CN LiClO4









N

NH

AcO

HN

HN

HN

HN

HN

NNH

AcO

N

NH

N

NH

NNH

N

NH

H

NNH

H

N

NH

N

NNH

Ac

Ac

Ac

Ac

Ac

N

NH

NN

N

NH

HO

HN

NNH

HO

OH

OH

N

NH

CHO

N

NH

HO

N

NNH

HO

HO

HOHOHO

Me

ab

c

d

ef

g

MeO2C

MeO2C

MeO2C

MeO2CMeO2C

CO2Me CO2Me

CO2Me

CO2Me

CO2MeCO2Me

CO2MeCO2Me

(64)

MeO2C

(68)

Ph

+

+

+

(23 28)

(51)(45)

(38)(70

)

(48 22)

(32)

40 56 57

58

58

59

6061

6263

64

NH2 middot HCl



3


-H2




O NaBH3


THF (reflux 3 h)


N

O

NH

NH

O

NH

NH

OCN

N

CN

HN HN HN

H

N

OBn

Bn

BnBn

X

NH

NH

N

O

NH

N

OBn

CN

OMe

NH

NH

N

O

NH

N

O

a

f

g

hi

j j

i

k

l m

2021 21 21

20 20

R 2R1

b c(828)

(83) 65 R1 = R2 = H66 R1 = Et R2 = Bn

+

d e(70) 67 X = OH

68 X = CN

CO2Et

CO2Et

CO2Et

(74)

(98)

(75)(97)

(trace)

(97)

(70)

(70)

(44)

OH OH

(79)


69 70

717225

27 73

29 31


2

CH2


3


Cl2


2


2



2

N=CH2

]Cl (15 equiv) CH2

Cl2


3



Cl2


2

SO4

(iii) NaBH4








N OH

N O N N O N OH N

N

OH

NH

NH

N

NH

O

NH

N

NH

O

N

NH

H

a b c d e

hf g

ij

(67)

Cbz Cbz Cbz Cbz

CbzCbz

Cbz

(93) (76)OEt

(91)OH

OH

OH

(93) OMe

Me

(48)

OTIPSOTIPS

OTIPS OTIPS

COOH

(100)

(77) (93)

H+

74 75 76 77 78 79

80 8281



4


SO4

Et2

O (rt 1 h) (c) N2

CH2


2

sdotC7

H8

(002 equiv) CH2

Cl2

(18 h) (d) (i) BF3

sdotOEt2

(015 equiv) CH2

Cl2



2




2

Cl2






5 Conclusions



Abbreviations




H

O

N

O

N

O

NH

N

O

NH

N

O

N

N

NH

R

N

NH

H

a

b

c

d

e

fg

i

h

j

TBDPSO TBDPSO

TBDPSO

+ OBn

OBn

OBn(84)

OR

(97) 87 R = H88 R = Ms

(80)

(80)

OTBDPSOTBDPSOTBDPS

OTBDPS

Boc

HO

Bn

BnBnBn

(58)

+(42)(97)

(87)

(48) 94 R = Bn95 R = H

(100)

OH


85 8689

90

67

919293

n-Bu3Sn


3

N (20 equiv) CH2

Cl2



2


2

(dba)3



3


O2


2


2

20 Pd (OH)2








N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)


CH2

CH2





3


O2


2



2

20 Pd (OH)2


N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)



2

CO3


2



2

=CHCH2


2

O2



4


O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

NH

AcO

HN

HN

HN

HN

HN

NNH

AcO

N

NH

N

NH

NNH

N

NH

H

NNH

H

N

NH

N

NNH

Ac

Ac

Ac

Ac

Ac

N

NH

NN

N

NH

HO

HN

NNH

HO

OH

OH

N

NH

CHO

N

NH

HO

N

NNH

HO

HO

HOHOHO

Me

ab

c

d

ef

g

MeO2C

MeO2C

MeO2C

MeO2CMeO2C

CO2Me CO2Me

CO2Me

CO2Me

CO2MeCO2Me

CO2MeCO2Me

(64)

MeO2C

(68)

Ph

+

+

+

(23 28)

(51)(45)

(38)(70

)

(48 22)

(32)

40 56 57

58

58

59

6061

6263

64

NH2 middot HCl



3


-H2




O NaBH3


THF (reflux 3 h)


N

O

NH

NH

O

NH

NH

OCN

N

CN

HN HN HN

H

N

OBn

Bn

BnBn

X

NH

NH

N

O

NH

N

OBn

CN

OMe

NH

NH

N

O

NH

N

O

a

f

g

hi

j j

i

k

l m

2021 21 21

20 20

R 2R1

b c(828)

(83) 65 R1 = R2 = H66 R1 = Et R2 = Bn

+

d e(70) 67 X = OH

68 X = CN

CO2Et

CO2Et

CO2Et

(74)

(98)

(75)(97)

(trace)

(97)

(70)

(70)

(44)

OH OH

(79)


69 70

717225

27 73

29 31


2

CH2


3


Cl2


2


2



2

N=CH2

]Cl (15 equiv) CH2

Cl2


3



Cl2


2

SO4

(iii) NaBH4








N OH

N O N N O N OH N

N

OH

NH

NH

N

NH

O

NH

N

NH

O

N

NH

H

a b c d e

hf g

ij

(67)

Cbz Cbz Cbz Cbz

CbzCbz

Cbz

(93) (76)OEt

(91)OH

OH

OH

(93) OMe

Me

(48)

OTIPSOTIPS

OTIPS OTIPS

COOH

(100)

(77) (93)

H+

74 75 76 77 78 79

80 8281



4


SO4

Et2

O (rt 1 h) (c) N2

CH2


2

sdotC7

H8

(002 equiv) CH2

Cl2

(18 h) (d) (i) BF3

sdotOEt2

(015 equiv) CH2

Cl2



2




2

Cl2






5 Conclusions



Abbreviations




H

O

N

O

N

O

NH

N

O

NH

N

O

N

N

NH

R

N

NH

H

a

b

c

d

e

fg

i

h

j

TBDPSO TBDPSO

TBDPSO

+ OBn

OBn

OBn(84)

OR

(97) 87 R = H88 R = Ms

(80)

(80)

OTBDPSOTBDPSOTBDPS

OTBDPS

Boc

HO

Bn

BnBnBn

(58)

+(42)(97)

(87)

(48) 94 R = Bn95 R = H

(100)

OH


85 8689

90

67

919293

n-Bu3Sn


3

N (20 equiv) CH2

Cl2



2


2

(dba)3



3


O2


2


2

20 Pd (OH)2








N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)


CH2

CH2





3


O2


2



2

20 Pd (OH)2


N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)



2

CO3


2



2

=CHCH2


2

O2



4


O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

O

NH

NH

O

NH

NH

OCN

N

CN

HN HN HN

H

N

OBn

Bn

BnBn

X

NH

NH

N

O

NH

N

OBn

CN

OMe

NH

NH

N

O

NH

N

O

a

f

g

hi

j j

i

k

l m

2021 21 21

20 20

R 2R1

b c(828)

(83) 65 R1 = R2 = H66 R1 = Et R2 = Bn

+

d e(70) 67 X = OH

68 X = CN

CO2Et

CO2Et

CO2Et

(74)

(98)

(75)(97)

(trace)

(97)

(70)

(70)

(44)

OH OH

(79)


69 70

717225

27 73

29 31


2

CH2


3


Cl2


2


2



2

N=CH2

]Cl (15 equiv) CH2

Cl2


3



Cl2


2

SO4

(iii) NaBH4








N OH

N O N N O N OH N

N

OH

NH

NH

N

NH

O

NH

N

NH

O

N

NH

H

a b c d e

hf g

ij

(67)

Cbz Cbz Cbz Cbz

CbzCbz

Cbz

(93) (76)OEt

(91)OH

OH

OH

(93) OMe

Me

(48)

OTIPSOTIPS

OTIPS OTIPS

COOH

(100)

(77) (93)

H+

74 75 76 77 78 79

80 8281



4


SO4

Et2

O (rt 1 h) (c) N2

CH2


2

sdotC7

H8

(002 equiv) CH2

Cl2

(18 h) (d) (i) BF3

sdotOEt2

(015 equiv) CH2

Cl2



2




2

Cl2






5 Conclusions



Abbreviations




H

O

N

O

N

O

NH

N

O

NH

N

O

N

N

NH

R

N

NH

H

a

b

c

d

e

fg

i

h

j

TBDPSO TBDPSO

TBDPSO

+ OBn

OBn

OBn(84)

OR

(97) 87 R = H88 R = Ms

(80)

(80)

OTBDPSOTBDPSOTBDPS

OTBDPS

Boc

HO

Bn

BnBnBn

(58)

+(42)(97)

(87)

(48) 94 R = Bn95 R = H

(100)

OH


85 8689

90

67

919293

n-Bu3Sn


3

N (20 equiv) CH2

Cl2



2


2

(dba)3



3


O2


2


2

20 Pd (OH)2








N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)


CH2

CH2





3


O2


2



2

20 Pd (OH)2


N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)



2

CO3


2



2

=CHCH2


2

O2



4


O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N OH

N O N N O N OH N

N

OH

NH

NH

N

NH

O

NH

N

NH

O

N

NH

H

a b c d e

hf g

ij

(67)

Cbz Cbz Cbz Cbz

CbzCbz

Cbz

(93) (76)OEt

(91)OH

OH

OH

(93) OMe

Me

(48)

OTIPSOTIPS

OTIPS OTIPS

COOH

(100)

(77) (93)

H+

74 75 76 77 78 79

80 8281



4


SO4

Et2

O (rt 1 h) (c) N2

CH2


2

sdotC7

H8

(002 equiv) CH2

Cl2

(18 h) (d) (i) BF3

sdotOEt2

(015 equiv) CH2

Cl2



2




2

Cl2






5 Conclusions



Abbreviations




H

O

N

O

N

O

NH

N

O

NH

N

O

N

N

NH

R

N

NH

H

a

b

c

d

e

fg

i

h

j

TBDPSO TBDPSO

TBDPSO

+ OBn

OBn

OBn(84)

OR

(97) 87 R = H88 R = Ms

(80)

(80)

OTBDPSOTBDPSOTBDPS

OTBDPS

Boc

HO

Bn

BnBnBn

(58)

+(42)(97)

(87)

(48) 94 R = Bn95 R = H

(100)

OH


85 8689

90

67

919293

n-Bu3Sn


3

N (20 equiv) CH2

Cl2



2


2

(dba)3



3


O2


2


2

20 Pd (OH)2








N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)


CH2

CH2





3


O2


2



2

20 Pd (OH)2


N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)



2

CO3


2



2

=CHCH2


2

O2



4


O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


H

O

N

O

N

O

NH

N

O

NH

N

O

N

N

NH

R

N

NH

H

a

b

c

d

e

fg

i

h

j

TBDPSO TBDPSO

TBDPSO

+ OBn

OBn

OBn(84)

OR

(97) 87 R = H88 R = Ms

(80)

(80)

OTBDPSOTBDPSOTBDPS

OTBDPS

Boc

HO

Bn

BnBnBn

(58)

+(42)(97)

(87)

(48) 94 R = Bn95 R = H

(100)

OH


85 8689

90

67

919293

n-Bu3Sn


3

N (20 equiv) CH2

Cl2



2


2

(dba)3



3


O2


2


2

20 Pd (OH)2








N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)


CH2

CH2





3


O2


2



2

20 Pd (OH)2


N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)



2

CO3


2



2

=CHCH2


2

O2



4


O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

O

O PhR

N NH

N

O

O

Ph

NH

N

O

O

Ph

N

NH

H

N

NH

OH

PhN

OH

NH

H

c

d

efg

96 R = CH2CH97 R = CH

a-b(66)

+

OTBDPS OTBDPS

Boc

90

(65)

98

(92)

OTBDPSOTBDPSOTBDPS

99

(62)

10095

(61rArr 100)


CH2

CH2





3


O2


2



2

20 Pd (OH)2


N

O

N

O

HO

N

O

NH

N

HO

I

Et EtEt

EtEtEt

O

OEt

NH

N

OH

NHH

a

b c

d

eg f

OTBS OTBS OTBS

OTBSOTBSOTBS

+

102

101

(80)

CO2Et CO2Et

103

(73)

104

(85)

105

(98)

106

(77)

N3

107

H2N

108

(78 rArr 107)



2

CO3


2



2

=CHCH2


2

O2



4


O (3 1 1vv) 40∘C (24 h)


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


NH

N

H N

CHO

NH

HO

N

NH

HO

OH

N

NH

H

OH

N

NH

H

OH

N

NH

H

OH

a b

16

c

d

CO2Me

CO2Me CO2Me CO2Me

CO2Me


5 steps(22)

40 41

(79 rArr 40)

109

(71)

110 C16-H120572111 C16-H120573

(4 1)

(90)

(+)-Goniomitine (1)




2

NH4


Cl OH

OO

OEt

OTf

OBn

COOMe

OBn

COOK

COOMe

OBnOH

OBn

N

OR

NHH

c

d g

hi

j

+

112 113 114

a-b(60)

OTBS OTBS(80)

115

(70)

NO2

NO2NO2

NO2NO2

118

119

e-f(91)

117116

(93)

(72)

N3

120

(80)

121 R = Bn(+minus)-1 R = H

(65)



2


2

CH2

OBn (12 equiv) Cs2

CO3


2


3


3

(50 equiv) MeOH O3





References





































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


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

Review Article Goniomitine: An Overview on the …downloads.hindawi.com/archive/2013/292396.pdfReview Article Goniomitine: An Overview on the Chemistry of This Indole Alkaloid JoséC.F.Alves