Review Article Goniomitine: An Overview on the Chemistry of This Indole Alkaloid - Hindawi

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ISRNOrganicChemistry
Volume2013,ArticleID292396,14pages
http://dx.doi.org/10.1155/2013/292396
Review Article
Goniomitine: An Overview on the Chemistry of
This Indole Alkaloid
JoséC.F.Alves
InstitutodePesquisasdeProdutosNaturaisWalterMors,CentrodeCieˆnciasdaSau´de,BlocoH,
UniversidadeFederaldoRiodeJaneiro,21941-902RiodeJaneiro,RJ,Brazil
CorrespondenceshouldbeaddressedtoJose´C.F.Alves;[email protected]
Received20September2013;Accepted22October2013
AcademicEditors:G.Li,F.Machetti,andJ.Wu
Copyright©2013Jose´C.F.Alves. This is an open access article distributed under the Creative Commons Attribution License,
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Thispaperreportsanoverviewonthechemistryoftheindolealkaloidgoniomitinefocusing,mainly,onthemethodsofsynthesis
relatedtothisnaturalproductandanalogs.
1.Introduction the same plant from where goniomitine had been isolated.
Therelativestructureofgoniomitine(1)wassoonaftercon-
Theindolealkaloidsbelongtotheclassofnaturalsubstances firmedbyTakanoetal.[8]throughthetotalenantioselective
displaying biological activities as well as a broad structural synthesis of the natural form of this alkaloid. It could be
diversity.Inviewoftheseimportantproperties,theseprod- evidenced that the absolute structure of the compound 1 is
uctsaretargetofstudyintheareasofisolation,identification, enantiomerictotheonethathadbeeninitiallyproposedfor
and synthesis [1–5]. Goniomitine (1) (Figure1) is an indole 20S,21Rconfiguration.
alkaloid that was isolated and identified by Randriambola
et al. [6] and Hashimoto and Husson [7]. The unique
structureandbiologicalactivityofgoniomitinehaveattracted 3.BiogenesisofGoniomitine
the attention of several groups. This review describes the
isolation, biogenesis hypothesis, chemical transformations, Randriambolaetal.[6]proposedthatgoniomitine(1)maybe
andsynthesesofthisalkaloidandanalogs. derivedfromtheAspidospermaskeletonofvincadifformine
(2)bythesuccessivestepsdepictedinScheme1.
2.IsolationofGoniomitine
4.ChemicalTransformationsand
In the course of studies of the alkaloids of the genus SynthesesofGoniomitineandAnalogs
Gonioma, Randriambola et al. [6] isolated, from the root
bark of Gonioma malagasy, a crystalline compound named 4.1.ChemicalTransformationsofGoniomitine. Fortheocca-
goniomitine with melting point of 150∘C (ether-methanol), sion of the structural determination of goniomitine (1) [6],
[C𝛼1]9DH2026−N820O∘(H(cRM0.9S,Min+∙C2H98C.2l03)8,0,acnadlcumlaoteledcfuolrar298fo.2rm04u5l)a. t5hiuspcoonmtproeautnmdewntaswtirtahnsAfoc2rmOeidninMtoeOthHeNan-daceintytoldtehreivNat,iOve-
Thestructureofgoniomitinewasinitiallyproposedasindi- diacetylderivative6upontreatmentwithAc2Oinpyridine
cated in Figure1, with 20S, 21R configuration, based on its (Scheme2). The formation of the acetylated compounds 5
NMRspectra.Itsabsolutestructurewasdeducedthroughthe and6confirmedthepresenceofthegroupsOHandNHin
correlationwithotheralkaloidsfromAspidospermafoundin thestructureof 1.
2 ISRNOrganicChemistry
OH OH
N N
S R R S
H H
21 20 21 20
H N H N
(20R, 21S)-(−)-Goniomitine (1) (20S, 21R)-(+)-Goniomitine (1)
(natural) (unnatural)
Figure1:Natural(−)-andunnatural(+)-goniomitine(1).
3 14
5 4N 15 HO H N HO H N+ OH
20 19
10 9 68271 H 116718 a-b H c
11 13 N1 2 CO2Me N+ N N
12
H H H H
4
2 3 4
N
H +
d
OH
6
9 8 7 5
10
2 16
11 1
13 N 17 18
12 21
H 20 19
H N4 15
3
14
1
Scheme1:Biogenetichypothesisoftransformationofvincadifformine(2)intogoniomitine(1):(a)oxidativefissionoftheC-5,N-4bond;(b)
decarboxylation;(c)retro-Mannichreaction;(d)nucleophilicattackoftheindolenitrogenontheiminiummoiety.
OH OH OAc
Ac2O Ac2O
MeOH Py
N N N
H H H
Ac N H N Ac N
5 1 6
Scheme2:Chemicaltransformationsofgoniomitine(1)intotheacetylderivatives5and6.
ISRNOrganicChemistry 3
OH OH OH
CH3
a b c d
(55%) (57%) (97%) (91%)
N H N N N N
H H H H
TMS
7 8 9 10 11
N N N N
Me + Me
−
I
e (59%)
OH
11 +
N
(36 : 23) H
Me N
(+/−)-12
Scheme3:Reagentsandconditions:(a)(i)n-BuLi(2.2equiv),hexane(reflux,6h)and(ii)methyl3-(3-pyridyl)propanoate,THF(−78to
∘
15C);(b)MeMgI(10equiv),ethyleneoxide(10equiv),Et2O(1h),reflux(2h);(c)MeI,CH2Cl2(reflux,2h);(d)H2,PtO2,MeOH(3h);(e)
H2,PtO2,NaOMe,MeOH(3h).
4.2. Synthesis of the Goniomitine Analog (+/−)-12. In order as a result of the attempts to synthesize (+)-goniomitine
to ascertain unambiguously the unprecedented structure of (1) from the compound 40, previously obtained from (−)-
the alkaloid goniomitine (1), Hashimoto and Husson [7] vincadifformine(2)(Scheme5)[9].InScheme7aredepicted
synthesizedthegoniomitineanalog(+/−)-12bythesequence thesequences ofreactionsthatled to thesynthesisofcom-
ofreactionsdepictedinScheme3. pound45aswellasotheralkaloidswithtetracyclicskeleton
ofgoniomitine(1).
4.3. Total Synthesis of (−)-Goniomitine by Takano. The first
enantiocontrolledtotalsynthesisofnatural(−)-goniomitine 4.6.SynthesisoftheGoniomitineAnalogs 52–55 byCycload-
(1) was published in 1991 by Takano et al. [8], who estab-
dition Reactions. In the year 1996, Gu¨rtler et al. [11] pub-
lished the absolute stereochemistry of this alkaloid. This lished the synthesis of the goniomitine analogs 52–55 by
total synthesis, depicted in Scheme4, starts with the chiral [4 + 2] cycloaddition reactions between 2-vinylindoles
cyclopentadienonesynthon(−)-13.
and substituted cyclic enamines, via anodic oxidation
(Scheme8).
4.4.TheFirstBiomimeticApproachtotheSkeletonofGoniomi-
tine from an Aspidosperma Alkaloid. The results from the
4.7.ProposalofSynthesisofGoniomitinebyAlves. Intheyear
study of biomimetic transformation of an Aspidosperma
alkaloid (2) into the substances 39-40, with the skeleton 2000,Alves[12]presentedhisqualificationexamofdoctorate
of goniomitine (1), were published in 1995 by Lewin et al. aboutaplanofsynthesisoftheindolealkaloidgoniomitine
(1). The convergent strategies and synthetic routes for the
[9]. The sequences of reactions for the discovery of a new
synthesis of this alkaloid, idealized on that occasion, are
biomimeticinvitrorearrangementaredepictedinScheme5.
described in the supplementary material of this review,
Scheme6 displays the proposed mechanism [9] for the
transformation of compound 36 into the alkaloids 39 and availableonlineathttp://dx.doi.org/10.1155/2013/292396.
40.
4.8. Syntheses of Cytotoxic Bisindole Alkaloids. In the year
4.5. Semisynthesis of (+)-(16S,20S,21R)-16-Hydroxymethyl- 2000,Lewinetal.[13]publishedanarticleaboutaslightmod-
goniomitine from (−)-Vincadifformine. In continuation to ificationoftheBorchreductiveaminationmethod(delayed
the studies of chemical transformations of vincadifformine addition of NaBH3CN) [14, 15], applied to compound 40,
(2) into alkaloids analogs to goniomitine (1), Lewin and analogofthenaturalalkaloidgoniomitine(1).Asaresultof
Schaeffer[10]publishedin1995thesemisynthesisof(+)-16- thisreaction,aseriesofnewcytotoxicbisindolealkaloidswas
hydroxymethyl-goniomitine(45).Thisalkaloidwasobtained prepared,asdepictedinScheme9.
4 ISRNOrganicChemistry
H a-c H d O e-f S O
H (53%) H (72%⇒14)
S
(−)-13 14
O O 15 16
I g-h (75%)
O
20 HN OEt O O O
MeO j-k MeO i MeO
(82%⇒17)
19 18 17
O S
l (81%) H S
CO2Me
+
O m
N OEt (81%) N N
21 H 22 H O (11 : 70) 23
O
OMe
n-p
CN N
r-s q
N O (78%⇒25) N O N O (65%⇒23) N NH2
H H H
27 HN 26 HN 25 HN 24 O
t
H OH
CN CN
O
u v-x y
N (84%⇒27) N N (40%⇒29) N
21
Cl− + H H H
HN HN HN HN
28 29 30
z 31: C21-H𝛽
(82%)
(−)-1: C21-H𝛼
Scheme4:Reagentsandconditions:(a)Zn(5.0equiv),AcOH-EtOH(1:3),reflux(4h);(b)EtI(2.0equiv),t-BuOK(1.2equiv),THF(−70to
−30∘C,15min);(c)allylbromide(2.0equiv),t-BuOK(1.2equiv),THF(−30∘C,5min);(d)o-dichlorobenzene(reflux,24h);(e)LiAlH4(1.0
equiv),CuI(0.5equiv),HMPA-THF(1:4),−75∘C(15min);(f)propane-1,3-diyldithiotosylate(1.5equiv),t-BuOK(3.0equiv),t-BuOH-THF
∘ ∘
(1:4),0C;(g)KOH(5.0equiv),t-BuOH(70C,12h);(h)CH2N2,Et2O;(i)MeI(1.0equiv),CaCO3(5.0equiv),10%aq.MeCN(reflux,1h);
(j)Ph3P(4.0equiv),CBr4(2.0equiv),Et3N(3.0equiv),CH2Cl2(0∘C,5min);(k)LDA(3.0equiv),THF(−78∘C,10min);(l)compound20(1.1
equiv),PdCl2(PPh3)2(2%),CuI(5%),Et3N(reflux,30min);(m)NaOEt(10equiv),Et3N(5%),EtOH(reflux,3h);(n)(i)dicyclohexylborane
∘ ∘
(1.5equiv),THF(0C,30min),(ii)10%NaOH(1.0equiv),30%H2O2(3.0equiv),0C(30min);(o)phthalimide(1.3equiv),Ph3P(1.3equiv),
(i-PrO2CN)2(1.3equiv),THF(0∘C,10min);(p)NH2NH2⋅H2O(4.0equiv),EtOH(reflux,2h);(q)[Me2N=CH2]Cl(1.5equiv),CH2Cl2(r.t.,
∘
30min);(r)MeI,MeOH(r.t.,10min);(s)NaCN(1.3equiv),DMF(100C,10min);(t)POCl3(6.0equiv),toluene(reflux,2h);(u)NaBH4,
MeOH,0∘C;(v)DIBAL(1.5equiv),CH2Cl2(−75∘C,10min);(x)dil.H2SO4;(y)NaBH4;(z)30%HCl-MeOH(1:10),reflux(30min).
ISRNOrganicChemistry 5
+ Ar O O
N MeO N N N
5 O 5
3 steps a
H H H H
(82%)
Cl Cl Cl
N CO2Me N CO2Me N CO2Me N CO2Me
H
2 32 33 34
Ar =m-Cl-C6H4
O
CHO CHO O N Ar O N
HO 5 O 5
CO2Me CO2Me e H b H
(53%) Cl (71%) Cl
N + N N CO2Me N CO2Me
H H 35a: C5-H𝛼
HO N (42 : 11) N O 36 35b: C5-H𝛽 (3 : 1)
40 f 39
(40%) c (100%)
g
(52%) O
Ar O N
O 5
h
H
(48%)
N CO2Me
H
37
d (18%)
O N
HO 5
H
N
38
−1
Scheme5:Reagentsandconditions:(a)m-CPBA(1.1equiv),CH2Cl2(r.t.,3h);(b)0.2molL NaOH-MeOH(r.t.,5min);(c)NaI(3.0equiv),
−1 ∘
AcOH(r.t.,1.5h);(d)11molL HCl(105C,10min);(e)TFA(16equiv),CH2Cl2(r.t.,20min);(f)TFA(r.t.,4h);(g)TFA(16equiv),CH2Cl2
(r.t.,15h);(h)TFA(12.5equiv),CH2Cl2(r.t.,45h).
In continuation to the studies of synthesis of cytotoxic synthesis of racemic (+/−)-goniomitine (1), accomplished
bisindole alkaloids, Raoul et al. [16] published, in the year in 17 linear steps with 5.2% overall yield starting from
2001, an article with a novel series of these alkaloids pre- commercially available 𝛿-valerolactam (65). Their synthetic
pared by reductive amination of the compound 40 with approachincludestheapplicationofaformal[3+2]cycload-
various anilines, using the modified Borch amination con- dition between the highly functionalized nitrile 68 and the
ditionsdescribedinScheme9(delayedaddition(20min)of activated cyclopropane 69 to prepare the indole nucleus
NaBH3CN)[15].Theinfluenceofsubstitutionofthestarting (Scheme10).
aniline on the reaction and on cytotoxicity of produced
dimersisdiscussedinthepaper.
4.10. Total Synthesis of (+/−)-Goniomitine by Waser. De
Simoneetal.[18]publishedthesynthesisofracemicgoniomi-
4.9.TotalSynthesisof(+/−)-GoniomitinebyPagenkopf. Inthe tine (1) with the first study of its bioactivity, revealing
year 2008, Morales and Pagenkopf [17] published the total significant cytotoxicity against several cancer cell lines [18,
6 ISRNOrganicChemistry
CHO
+
−
O N HO N: O N CO2Me
HO TFA OHC OHC Cl
H H
CH2Cl2 N
Cl Cl Cl
H
N CO2Me N CO2Me N CO2Me − +
O N
36 36a H 36b 36b
CHO CHO CHO
CO2Me CO2Me CO2Me
b + a
N N N
b H
H H
−
N O N O −O +N
36d 36c
39
a
TFA
CHO CHO CHO
CO2Me CO2Me CO2Me
.. OCOCF3
N N+ H N
H H H
HO N −O N HO N
39a 39b 40
Scheme6
OH OH
CHO
CO2Me CO2Me CO2H
N a N b N
(62%) (43%)
H H H
HO N HO N HO N
40 41 42
c (57%)
OH OH OH OH
OH OH OH CH3
H H
N d N e N f N
H (35%) H (66%) H (75%) H
HO N HO N H N H N
43 44 45 46
∘
Scheme7:Reagentsandconditions:(a)NaBH3CN,AcOH(r.t.,1.5h);(b)NaOH-MeOH(120C,1h);(c)LiAlH4(excess),THF(reflux,3h);
∘
(d)H2(1atm),10%Pd-C,MeOH(r.t.,5h);(e)TiCl3-H2O,MeOH(r.t.,20h);(f)30%HCl-MeOH(120C,1.5h).
ISRNOrganicChemistry 7
Me
CN
N
Me
H CO2Me
Me N
55
d(62%)
Me R1 R3 Me
CN c CN + R2 N a CN
(91%) (68%)
N Me NH N Me
HHN CO2Me 49: R2= H, R3= CN HHN CN
47: R1= Me 50: R2= H, R3= CO2Me
54 48: R1= (CH2)2OEt 51: R2= Me, R3= CO2Me 52
b (53%)
OEt
CN
N
Me
H CN
H N
53
Scheme 8: Reagents and conditions: (a) vinylindole 47 (1.0 equiv), enamine 49 (2.37 equiv), CH3CN, LiClO4 (0.1mol L−1), electrolysis
(480mVversusAg/AgNO3,current(20to2mA),200min);(b)vinylindole48(1.0equiv),enamine49(6.17equiv),CH3CN,LiClO4(0.1mol
L−1),electrolysis(480mVversusAg/AgNO3,current(20to2mA),200min);(c)vinylindole47(1.0equiv),enamine50(1.4equiv),CH3CN,
LiClO4(0.1molL−1),electrolysis(480mVversusAg/AgNO3,current(20to2mA),40min);(d)vinylindole47(1.0equiv),enamine51(2.1
−1
equiv),CH3CN,LiClO4(0.1molL ),electrolysis(480mVversusAg/AgNO3,current(20to2mA),200min).
19]. The strategy of this synthesis is based on cyclization Using the synthetic route described in Scheme13, but
of aminocyclopropanes [20], applied to cyclopropyl ketone startingfromtheenantiomerofthelactam97(ent-97)Mizu-
83 to lead to compound 84 with tetracyclic skeleton of tani et al. [21] synthesized the unnatural (+)-goniomitine
goniomitine(Scheme11). (ent-1).Withtheracemic,natural,andunnaturalgoniomitine
inhand,theauthors[21]executedthepreliminarybioactive
assays, which revealed that natural (−)-goniomitine has
4.11. Total Syntheses of (+/−)-, (−)-, and (+)-Goniomitine by
strongerantiproliferativeactivityinMockandMDCK/MDR1
Mukay. In the year 2011, Mizutani et al. [21] published the
cellsthanitsenantiomer.
syntheses of both racemic and optically active goniomitine,
whoseprincipalstepsarethepreparationoftheindoleskele-
tonbytheirowndevelopedprocedure[22]andalkenecross- 4.12. Total Synthesis of (+/−)-Goniomitine by Bach. In the
metathesis. The synthesis of racemic (+/−)-goniomitine (1) year 2012, Jiao et al. [23] published the total synthesis of
was performed, as a preliminary study, by the sequence of racemic goniomitine (1), using the strategy of C-2 alkyla-
reactionsdepictedinScheme12. tion of indoles catalyzed by palladium via a norbornene-
The convergent total synthesis of the natural (−)-goni- mediated C–H activation [24]. The steps for the synthesis
omitine(1)[21]wascompletedbythesequenceofreactions of (+/−)-goniomitine (1), by this strategy, are depicted in
depictedinScheme13. Scheme14.
8 ISRNOrganicChemistry
MeO2C MeO2C
Me N HN
N N
CO2Me H N CO2Me H N
HO AcO
N N
H 63 H 62
HO N AcO N
e(68%)
f
(64
%)
MeO2C
HN
HN Ph
CHO
N
CO2Me CO2Me CO2Me H N
NH2·HCl HO
N + N + N
58 b H a H H
(45%) HO N (51%) HO N HO N
40 56 57 (23 : 28) 58
c(38%)
g
%)
(32
OH
MeO2C
HN HN
OH N N
H N CO2Me H N
HO H
N N
H H
HO N H N
64 59
d %)
(70
MeO2C MeO2C
HN Ac N
N N
CO2Me N + CO2Me H N
Ac Ac
N N
H H
Ac N (48 : 22) Ac N
61 60
Scheme9:Reagentsandconditions:(a)compound56(5.0equiv),NaBH3CN(immediateaddition),MeOH(r.t.,16h);(b)compound56(5.0
equiv),NaBH3CN(delayedaddition,20min),MeOH(r.t.,16h);(c)TiCl3-H2O(6.0equiv),MeOH(r.t.,20h);(d)Ac2O,Py(r.t.,48h);(e)
Ac2O,Py(r.t.,3h);(f)CH2O,NaBH3CN,AcOH(r.t.,2h);(g)LiAlH4,THF(reflux,3h).
ISRNOrganicChemistry 9
O O
R1 R2 X Bn CO2Et O
N (82b.,8 c%) N + CO2Et (74f%) N Bn
N
a 65: R1= R2= H d, e 67: X = OH 69 OMe H
(83%) 66: R1= Et, R2= Bn (70%) 68: X = CN 70
g (98%)
CO2Et
O O O
i h
Bn Bn
N NH (97%) N N (75%) N N
H H H
25 72 71
j (trace) j (70%)
CN CN
O O
i
Bn
N NH (97%) N N
H H
27 73
k (70%)
OH OH
CN
l m
(44%) (79%)
N N N
H 21 H 21 H 21
20 20 20
HN HN HN
29 31 (+/−)-Goniomitine (1)
Scheme10:Reagentsandconditions:(a)(i)n-BuLi(2.0equiv),THF(−78∘C),(ii)EtI(1.0equiv),−78∘C(1h),(iii)BnBr(1.0equiv),r.t.
(overnight);(b)(i)LDA(1.0equiv),THF(−78∘C,15min),(ii)BrCH2CH2OTHP(1.1equiv),r.t.(overnight);(c)TsOH(0.1equiv),MeOH(ice-
brinebath,4h);(d)Et3N(2.1equiv),MsCl(1.0equiv),CH2Cl2(0∘Ctor.t.,3h);(e)NaCN(2.0equiv),MeCN,120∘C(𝜇w,8h,900rpmstirring);
(f)Nitrile68(1.0equiv),cyclopropane69(2.9equiv),TMSOTf(1.0equiv),EtNO2(−30∘C,24h);(g)5%Pd-C(0.03equiv),mesitylene(reflux,
24h);(h)NaOH(10equiv),EtOH-H2O(1:1),150∘C(𝜇w,3h,900rpmstirring);(i)Na(5.0equiv),liq.NH3(0.042molL−1),THF(−78∘C,
∘
10min);(j)(i)[Me2N=CH2]Cl(1.5equiv),CH2Cl2(r.t.,15min),(ii)MeI(40equiv),MeOH(r.t.,10min),(iii)NaCN(1.3equiv),DMF(100C,
10min);(k)(i)POCl3(6.0equiv),toluene(reflux,2h),(ii)NaBH4(2.0equiv),MeOH(0∘C,30min);(l)(i)DIBAL(1.5equiv),CH2Cl2(−78∘C,
−1 ∘
10min),(ii)0.75molL H2SO4,(iii)NaBH4(2.2equiv),EtOH(0C,30min);(m)TsOH(cat.),Et3N-MeOH(3:5,v/v),reflux(30min).
4.13. Synthesis of (+)- and (−)-Goniomitine by Lewin. In thesameconditionsdescribedinScheme15.Theevaluation
the year 2013, Lewin et al. [25] have published the first oftheantiproliferativeeffectof(+)-and(−)-goniomitine(1),
biomimetic semisynthesis of goniomitine (1), in nine steps undertakenonfivehumancancercelllines,hasdemonstrated
with 11% overall yield, starting from vincadifformine (2). that unnatural (+)-goniomitine is more potent than its
Natural (−)- and unnatural (+)-goniomitine were prepared enantiomer(−)-goniomitine[25],inoppositiontoMizutani
from(+)-and(−)-vincadifformine,respectively.Thestepsfor etal.’sresultsonacaninekidneycellline(MDCKII)[21].
thesynthesisofunnatural(+)-goniomitine(1)aredepictedin
Scheme15. 4.14. Synthesis of (+/−)-Goniomitine by Zhu. In the year
Lewin et al. [25] have synthesized the natural (−)-goni- 2013, Xu et al. [26] have published a seven-step total
omitine(1),startingfrom(+)-vincadifformine(ent-2),using synthesis of (+/−)-goniomitine (1) through two key steps:
10 ISRNOrganicChemistry
H Cbz Cbz Cbz Cbz Cbz
N O a N O b N c N O d N H O e N H O
(67%) (93%) (76%) (91%) (93%)
OMe
OEt OH N
74 75 76 77 78 79
Me
OH OTIPS OTIPS
f g
(100%) h (48%)
N N N
H H
80 81 82 COOH
OH OTIPS OTIPS
+
H
j O O
i
(77%) (93%)
N N N
H H H
H
H N Cbz N
N
Cbz
(+/−)-Goniomitine (1) 84 83
∘ ∘
Scheme11:Reagentsandconditions:(a)(i)n-BuLi(2.2equiv),THF(0C,30min),(ii)EtI(1.5equiv),0C(20min),(iii)benzylchloroformate
∘ ∘
(1.05equiv),0C(20min);(b)(i)NaBH4(1.05equiv),MeOH(0C,15min),(ii)conc.H2SO4,Et2O(r.t.,1h);(c)N2CH2COOEt(4.0equiv),
(CuOTf)2⋅C7H8 (0.02equiv),CH2Cl2 (18h);(d)(i)BF3⋅OEt2 (0.15equiv),CH2Cl2 (−20to0∘C),(ii)NaOH(9.0equiv),H2O-THF-EtOH
∘ ∘
(1:1:3),0Cto60C(2h);(e)(i)DMTMM(1.5equiv),THF(r.t.,60min),(ii)MeNHOMe.HCl(1.0equiv),NMM(2.0equiv),r.t.(36h);(f)
∘ ∘
TIPSCl(1.05equiv),imidazole(2.1equiv),DMF(r.t.,1h);(g)(i)n-BuLi(1.2equiv),Et2O(0Cthenreflux,2h),(ii)CO2(0C,30min),(iii)
H3O+(pH2);(h)(i)t-BuLi(3.0equiv),compound82(1.5equiv),TMEDA(2.0equiv),THF(−78∘C,3h),(ii)amide79(1.0equiv),THF(0∘C,
∘
20min);(i)TsOH(0.2equiv),CH2Cl2(r.t.,10min);(j)(i)NaBH4,MeOH(0Ctor.t.,3h),(ii)Ac2O,Py(r.t.,overnight),(iii)H2,Pd-C(0.1
equiv),EtOH,(iv)TBAF(4.4equiv),THF(r.t.,30min).
(i) a novel palladium-catalyzed decarboxylative coupling of new efficient enantioselectivesynthetic strategies for this
reaction between the potassium nitrophenyl acetate 118 indolealkaloid,withlowoperationalcosts,isstillatargetto
and the vinyl triflate 115 for a rapid production of the bereached.
functionalized cyclopentene 119; (ii) a late-stage construc-
tion of the whole tetracyclic scaffold of goniomitine (1)
from the functionalized cyclopentene 120 by a one-pot
Abbreviations
integratedoxidation/reduction/cyclization(IORC)sequence
(Scheme16).
Ac: Acetyl
9-BBN: 9-Borabicyclo[3.3.1]nonane
Boc: tert-Butoxycarbonyl
5.Conclusions
Bn: Benzyl
n-Bu: n-Butyl
In summary, it may be concluded that this brief survey
on the chemistry of goniomitine has covered the literature t-Bu: tert-Butyl
relative to this alkaloid and analogs from 1987 to the first Bz: Benzoyl
semester of the year 2013. Taking into account the results DIAD: Diisopropylazodicarboxylate
published in this period, a considerable progress on the
DIBAL: Diisobutylaluminumhydride
synthesis of this alkaloid has been verified in the last years
DMF: N,N-Dimethylformamide
(2008–2013) with the publications of five racemic and two
DMSO: Dimethylsulfoxide
enantiomericsyntheses.Itisalsoimportanttoemphasizethe
recent pioneering works on the bioactive assays performed DMTMM: 2,4-Dimethoxy-6-(4-methylmorpholin-4-
with the racemic mixtures as well as both enantiomers of ium-4-yl) chloride
goniomitine. In spite of these progresses, the development DPPA: Diphenylphosphorylazide