Bioactive Natural Products

451 Pages·2016·15.697 MB·English

by  Atta-ur-Rahman (editor)

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Contributors
NumbersinParenthesesindicatethepagesonwhichtheauthor’scontributionsbegin.
A.F. Barrero (1), Institute of Biotechnology, University of Granada, Avda.
Fuentenueva, Granada, Spain
R. Braz-Filho (231), Laborato´rio de Ci^encias Qu´ımicas, Centro de Ci^encias e
Tecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos
dos Goytacazes; ICE, Universidade Federal Rural do Rio de Janeiro, Serop(cid:2)edica,
Brazil
S.M.Cardoso(65),CERNAS,SchoolofAgriculture,PolytechnicInstituteofCoimbra
Bencanta, Coimbra;University ofAveiro, Aveiro, Portugal
M.D. Catarino (65), CERNAS, School of Agriculture, Polytechnic Institute of
Coimbra Bencanta, Coimbra,Portugal
G. Chen (209), School of Life Science and National Glycoengineering Research
Center, Shandong University, Jinan; Center for Gene and Cell Engineering,
Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced
Technology, Chinese Academyof Sciences, Shenzhen,PR China
K. Chen (209), School of Life Science and National Glycoengineering Research
Center,ShandongUniversity,Jinan;AnhuiProvincialEngineeringResearchCenter
for Polysaccharide Drugs,Wannan Medical College,Wuhu, PRChina
A.R.deCarvalhoJr.(231),Laborato´riodeCi^enciasQu´ımicas,CentrodeCi^enciase
Tecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos
dos Goytacazes, Brazil
M.G. de Carvalho (231), ICE, Universidade Federal Rural do Rio de Janeiro,
Serop(cid:2)edica,Brazil
D.D´ıez(137),FacultaddeCienciasQu´ımicas,UniversidaddeSalamanca,Salamanca,
Spain
P.W.Dhore (287),Rashtrasant Tukadoji MaharajNagpurUniversity, Nagpur, India
V. Domingo (1), Institute of Biotechnology, University of Granada, Avda.
Fuentenueva, Granada, Spain
I. Duttagupta (29), Indian Association for the Cultivation of Science, Kolkata, West
Bengal, India
B. Fenert(399),Apteka “Dbamo Zdrowie”, Szczecinek, Poland
H.Gao(347),InstituteofTraditionalChineseMedicineandNaturalProducts,College
of Pharmacy,JinanUniversity, Guangzhou, PR China
xi
xii Contributors
K.C. Ghosh (29), Indian Association for the Cultivation of Science, Kolkata,
WestBengal, India
A. Gil-Meso´n (137), Facultad de Ciencias Qu´ımicas, Universidad de Salamanca,
Salamanca,Spain
J.N.Jacob(101),OrganomedCorporation, Coventry, RI,UnitedStates
V. Karuppiah (417), Marine Biotechnology Laboratory, State Key Laboratory of
Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai
JiaoTongUniversity, Shanghai, PRChina
D.M.Kokare(287),RashtrasantTukadojiMaharajNagpurUniversity,Nagpur,India
U.R.Lal(263),Birla InstituteofTechnology, Ranchi, Jharkhand, India
C.Li(209),AnhuiProvincialEngineeringResearchCenterforPolysaccharideDrugs,
WannanMedical College, Wuhu,PRChina
J. Li (347), State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants
Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry,
ChineseAcademyof Sciences, Urumqi, PRChina
Z. Li (417), Marine Biotechnology Laboratory, State Key Laboratory of Microbial
Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong
University, Shanghai,PR China
H. Makabe (323), Sciences of Functional Foods, Graduate School of Agriculture,
ShinshuUniversity, Kami-ina, Nagano, Japan
I.S. Marcos (137), Facultad de Ciencias Qu´ımicas, Universidad de Salamanca,
Salamanca,Spain
R.F. Moro (137), Facultad de Ciencias Qu´ımicas, Universidad de Salamanca,
Salamanca,Spain
J.F. Quilez del Moral (1), Institute of Biotechnology, University of Granada, Avda.
Fuentenueva,Granada, Spain
A.Rabahi(65),CentredeRechercheScientifiqueetTechniqueenAnalysesPhysico-
ChimiquesCRAPC, Bou-Ismail,Tipaza,Algeria
N.A.Raut(287),Rashtrasant Tukadoji Maharaj NagpurUniversity, Nagpur,India
S.D.Saoji (287),Rashtrasant Tukadoji MaharajNagpurUniversity, Nagpur, India
A.M.S.Silva(65), Universityof Aveiro, Aveiro, Portugal
A.Singh (263),Herbal Consultant,Phase-VII, Mohali,Punjab,India
S.Sinha(29),IndianAssociationfortheCultivationofScience,Kolkata,WestBengal,
India
W.Sun (417), Marine Biotechnology Laboratory,State Key Laboratory of Microbial
Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong
University, Shanghai,PR China
O.Talhi (65), Universityof Aveiro, Aveiro, Portugal
I.J.C. Vieira (231), Laborato´rio de Ci^encias Qu´ımicas, Centro de Ci^encias e
Tecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos
dosGoytacazes, Brazil
Contributors xiii
M.B.Zarzycka (399),Apteka “Bursztynowa”, Koszalin, Poland
P.K.Zarzycki(399),SectionofToxicologyandBioanalytics,KoszalinUniversityof
Technology, Koszalin, Poland
H. Zhao (347), Institute of Traditional Chinese Medicine and Natural Products,
College of Pharmacy,JinanUniversity, Guangzhou, PR China
J.Zou(347),InstituteofTraditionalChineseMedicineandNaturalProducts,College
of Pharmacy,JinanUniversity, Guangzhou, PR China
Preface
The exploration of bioactive molecules from natural resources continues to
play a major role in developing novel natural products of therapeutic signifi-
cance. Volume 48 of Studies in Natural Product Chemistry presents many
interesting classes of natural products with exciting biological activities.
Inthepastcentury,remarkablecreativityhasbeenachievedinthesynthesis
of structurally complex natural products. In the first chapter, Domingo et al.
havepresentedsomerecentaccomplishmentsinthetotalsynthesisofdifferent
familiesofnaturalproductsthroughC–Hfunctionalizationstrategies.
Nonribosomal peptides (NRPs) comprise a large group of pharmacologi-
callyimportant natural products, mostly isolated from microorganisms. Now-
adays, special importance has been given to their isolation and chemical
synthesis for their use as antibiotics, immunosuppressants, etc. Sinha et al.
have discussed the chemical synthesis of these NRPs in Chapter 2.
Flavonoids are polyphenolic compounds with very diverse roles. They
occur ubiquitously in food plants and vegetables. In Chapter 3, Cardoso
etal.havediscussedthebasicchemistryofflavonoids,structure–affinityrela-
tionship between flavonoids and key inflammatory markers, as well as an
approach to some synthetic strategies targeting the enhancement antiinflam-
matory properties of flavonoids.
The two major rhizomes, turmeric (Curcuma longa) and ginger (Zingiber
officinale), originated from the same family, Zingiberaceae, are known to
have a variety of medicinal and biological properties. In Chapter 4, Jacob
hasprovided acomparative accountofthestructuralandbiochemicalproper-
ties of volatile and nonvolatile fractions of turmeric and ginger.
Marcos et al. have discussed a complete biogenetic classificationof diter-
penes that have a 7-6-5 tricarbocyclic system in Chapter 5. A biosynthetic
approach to each group and synthetic approaches that have not been reported
previously are presented.
Fructooligosaccharides (FOSs) are oligosaccharides that are composed of
linearchainsoffructoseunits,linkedbybeta(2-1)bonds.Theyexhibitanum-
berofinterestingproperties,includingalowsweetnessintensity;theyarealso
calorie free, noncariogenic and are considered as soluble dietary fibers. Chen
etal.havereviewedthemechanismofactionandeffectsofFOSswithempha-
sisontherelationshipbetweentheprebioticeffectsandthebenefitstohealthin
Chapter6.
xv
xvi Preface
In Chapter 7, Vieira et al. have provided a review on the world’s largest
genus,Psychotria,withnearly2000species,mainlyfoundintropicalandsub-
tropical regions of the globe. They have presented the chemical, biological,
and synthetic aspects of compounds found in this genus.
The diseases that are mostly prevalent in tropical and subtropical regions
can be cured efficiently by the natural product-based drugs. Lal and Singh
have discussed, in Chapter 8, the trends during the last 5 years (2008–13) in
thediscoveryanddevelopmentofnaturalproduct-baseddrugsagainsttropical
diseases.
The epidemic rise in the number of patients suffering from Diabetes
mellitusrequirespromptactionfordiscoveringnewremediesespeciallyfrom
bioactive natural resources. In Chapter 9, Raut et al. have presented a review
focusingtheimportanceofbioactivenaturalproductsforthetreatmentofthis
disease. Prodelphinidins have many significant biological activities such as
antitumor,antiviral,andantiinflammatory.Acomprehensivediscourseoniso-
lation, synthesis, and biological activities of prodelphinidins is presented by
Makabe in Chapter 10. Gao et al. have presented a detailed review on the
source, chemistry, bioactivities, and biosynthetic pathway of natural products
from endolichenic fungi in Chapter 11.
Cyanobacteria (blue-green algae) are photosynthetic prokaryotes that are
excellent source of vitamins and proteins. Many cyanobacteria produce com-
pounds with potent biological activities. In Chapter 12, Zarzycki et al. have
provided general information about active metabolites from cyanobacteria
and particularly about the use of such biological materials as the ingredients
in food and pharmaceutical formulations.
Actinomycetes are one of the most efficient groups of secondary metabo-
lite producers which play a significant role in pharmaceutical applications.
Around 150 natural products have been isolated so far from these ubiquitous
actinobacteria. Li et al. have presented a review on the natural products
isolated from marine actinomycetes.
I am confident that this volume will prove to be of great interest to scien-
tists working in the field of medicinal chemistry and natural product
chemistry.
I would like to thank Ms. Taqdees Malik and Ms. Humaira Hashmi
for their assistance in the preparation of this volume. I am also grateful to
Mr. Mahmood Alam for the editorial assistance.
Atta-ur-Rahman, FRS
International Center for Chemical and Biological Sciences
H.E.J. Research Institute of Chemistry
University of Karachi
Karachi 75270
Pakistan
Chapter 1
Recent Accomplishments in the
Total Synthesis of Natural
Products Through C–H
Functionalization Strategies
V. Domingo*, J.F. Quilez del Moral and A.F. Barrero*
InstituteofBiotechnology,UniversityofGranada,Avda.Fuentenueva,Granada,Spain
Chapter Outline
Introduction 1 Miscellaneous 15
RadicalC–HFunctionalization 3 Azidationof
((cid:1))-Leuconoxine 3 TetrahydrogibberellicAcid 15
Ouabagenin 5 (+)-MyrrhanolC 17
GracilioetherF 7 ComplanadinesAandB 20
Metal-CatalyzedC–H (+)-HongoquercinA 23
Functionalization 9 ConcludingRemarks 25
Podophyllotoxin 9 References 26
DictyodendrinAand
DictyodendrinB 10
INTRODUCTION
C–HfunctionalizationisthetermusedtodescribetheabilitytocleaveaC–H
bond in a molecule regio- and stereoselectively and thereby transform it into
new C–C, C–X (X¼nitrogen, oxygen, or halogen), or C–metal bonds.
These transformations can be also classified according to the chemical
species generated as radical, radical-cationic, radical-anionic, carbenic, cat-
ionic, or metal-catalyzed transformations (the term C–H activation is used
in the last case). A considerable number of reactions and their applications
in synthesis have already been described and reviewed covering different
types of processes [1–5]. The field of C–H functionalization appears to offer
the synthetic chemist the opportunity to find new disconnections almost at
*Co-authorsofthischapter.
StudiesinNaturalProductsChemistry,Vol.48.http://dx.doi.org/10.1016/B978-0-444-63602-7.00001-1
©2016ElsevierB.V.Allrightsreserved. 1
2 StudiesinNaturalProductsChemistry
will within a multitude of covalent C–H bonds. Most C–H transformations
havebeenuncoveredrelativelyrecently.Asaresult,thesemodesofactivation
arebeingappliedatpresentinmaterialscience,agrochemistry,drugdevelop-
ment, perfumery, and the realm of natural products discussed in this chapter
(Fig. 1.1). The steady growth and refinement of C–H functionalization is
based mainly on the high level of originality and creativity in the disconnec-
tion approach to complex organic architectures.
Inanothersense,thetransformationofaC–Hbondintoabondwithadif-
ferent function is nothing new. It has been present in natural processes for
millennia and in natural product synthesis we are simply trying to emulate
thelevelofsyntheticefficiencyfoundinthenaturalworld.Naturecangener-
ate hydroxyls (P450 oxidases) [6–9], halides (halogenases) [10–12], amines
(transaminase and aminoacid dehydrogenase enzymes) [13–16] or construct
new C–C bonds (cyclases) [17–21] with surgical precision.
Technologically,themostpowerfulsyntheticstrategywouldbetotakean
enzymeanduseitineveryreactioninasyntheticsequenceasasimplechemi-
cal.However,enzymeengineeringhasnotyetachievedthelevelsofefficiency
that are needed to transform diverse molecular cores and experimentation in
enzymeengineeringanddirectevolutionarestillmandatory[22,23].
Historically, the application of C–H functionalization in natural products
dates from the early studies of steroids. In the early 1960, the Nobel prize
winnerSirDerekBarton(1969forhiscontributionto“conformationalanaly-
sis”)found awide range ofnewreactionsapplicabletohydrocarbons.Inpar-
ticular,thediscoveryofaremotenitriteradicalfunctionalizationenabledhim
to obtain aldosterone acetate in scalable amounts for the first time [24].
The birth of C–H functionalization was also assisted at that stage by other
chemists including Breslow, Corey, Arigoni, and Woodward (For a review
see Ref [25] and references cited therein).
Fromthosetimestothepresentera,C–Hfunctionalizationhasbeenincreas-
ingly exploited in the synthesis of natural products and reviewed recently
[3,26,27],sotheaimofthischapteristohighlightthemostrecentachievements
in this field. A number of molecules have been selected to illustrate the
Natural product
Pharmaceutical Material
synthesis
targets science
Perfumery C–H activation Agrochemistry
C–C, C–X
FIG.1.1 C–Hactivationfield.
RecentAccomplishmentsintheTotalSynthesis Chapter 1 3
diversification that has taken place in terms of the range of natural products
(their biosynthetic origin) and the C–H functionalization strategies executed
in their construction. Although highly desirable, it is impossible to cover all
the contributions that have appeared, and the authors apologize for any
omissions.
RADICAL C–H FUNCTIONALIZATION
(2)-Leuconoxine
((cid:1))-Leuconoxine (1) isgrouped as a monoterpene indole alkaloid (over 2000
described) [28] that is characterized by a singular congested diaza[5.5.6.6]
fenestrane skeleton (Fig. 1.2). Leuconoxine (1) belongs to the subfamily of
Aspidospermaalkaloids,andthisnaturalproductwasfirstfoundintheleaves
and stems of plants of the genus Leuconotis (eugenifolius and griffithii) in
Malaysia and Indonesia [29,30]. Due to their important range of bioactivities
(anticancer, antimalarial, and antiarrhythmic) as well as the challenging
scaffolds, indole alkaloids have stimulated the synthetic community and the
interest in ((cid:1))-leuconoxine (1) has resulted in five syntheses [31]. In 2015,
Gaich’s group synthesized thismolecule using as its key strategy a novel pho-
toinduceddominomacrocyclization/transannularcyclization[31](Scheme1.1).
ThecongestedABC-ringsystemof1wasassembledinalatestageusinga
Witkopcyclization,aphotochemicalC–Hfunctionalizationprocess.Thesyn-
theticsequencecommencedwiththesynthesisofthequiralmethylketone1a
using previously described methods. 1a was afterward transformed into the
b-ketosulfide 1b via conversion to the silyl enol ether, electrophilic addition
of bromine, and treatment of the bromoketone with dimethylsulfide (90%
yield,threesteps)(Scheme1.1).Then,1bwassubmittedtoGassman’sindole
synthesis conditions obtaining the indole core 1c in excellent yield (77%).
After experimenting with several conditions to remove the thiol in 1c and
applying aroutine setof reactions, they were ready toorchestratethe Witkop
photochemical reaction in the a-chloroacetamide 1f.
Irradiationof1fat254nmenabledtheWitkopphotocyclization,affording
a regioisomeric mixture of compounds, including indolophanes (2,4) 1g and
Witkop cyclization
O
H N BN
C
A
N N
D
O
(–)-Leuconoxine (1) Diaza [5.5.6.6] fenestrane skeleton
FIG.1.2 ((cid:1))-Leuconoxine.
4 StudiesinNaturalProductsChemistry
(a) NEt3, TMSOTf,
O O CH2Cl2 O O (d) aniline, –45°C, CH2Cl2, SMeO
(b) NBS, THF MeS MeCN, tBuOCl OEt
OEt (c) SMe2, toluene, 80°C OEt then NEt3, then H3PO4
N
90% 77% H
1a 1b 1c
O
(e) TFA, thiosalicylic acid, 88% CN NH
(f) DIBAL-H; (g) DMSO, SO3.Py Cl (l) BH3.SMe2, THF,
(h) Ph3PKCHCN, toluene, 80°C (i) Mg, MeOH, 85% then NaBO3, 51%
73% (3 steps) N N
H H
(j) LiAlH4, Et2O
O
1d (k)Cl OHDIC, DMAP 1e
73% (2 steps)
O
NH Cl O O
Cl
(m) hu (254 nm), Na2CO3, HN Witkop HN Transannular
MeOH, rt cyclization cyclization
NH 49% NH –Cl– NH
5:2.5:1:1
HO HO HO
1f
O
NH
O HN OH
O N HN
H
Trcayncsliaznantiuolnar H HN HO 1g 1h
+
N O O
H H H
HO N N
Transient iminium ion N N
H H
1i OH HO 1j
SCHEME1.1 Syntheticsequence.
H O H O H O
N (n) TPAP, NMO, MeCN N N
N N N
H 50%
HO HO O
1j (–)-Leuconoxine (1)
SCHEME1.2 ((cid:1))-Leuconoxineendgame.
(2,7) 1h together with the desired cyclized product at position C-3 in the
heterocycle 1j.
ThekeyC–Hfunctionalizationstepfeaturesaphotoinducedelectrontrans-
ferfromtheexcitedstateoftheindolicsystemtothechloroacetamidemoiety.
Thus, the diradical cation cyclises forming a transient iminium ion that
is trapped intramolecularly affording compounds 1i and 1j (Scheme 1.2).