Table Of ContentTopics in Heterocyclic Chemistry 57
Series Editors: Bert Maes · Janine Cossy · Slovenko Polanc
László Somsák Editor
Carbohydrate-spiro-
heterocycles
57
Topics in Heterocyclic Chemistry
SeriesEditors:
BertMaes,Antwerp,Belgium
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László Somsák
Editor
Carbohydrate-
spiro-heterocycles
With contributions by
(cid:1) (cid:1) (cid:1) (cid:1)
J.-B. Behr P. Compain D. Hazelard R. Hensienne
(cid:1) (cid:1) (cid:1) (cid:1)
S. Josse A. Martín N. Pellegrini-Moïse M. Pommier
(cid:1) (cid:1) (cid:1) (cid:1)
D. Postel M. Richard H. Rodríguez-Solla R. Soengas
(cid:1) (cid:1) (cid:1) (cid:1)
M. Soto P. R. Sridhar E. Suárez S. Vidal
Y. Yamamoto
Editor
LászlóSomsák
DepartmentofOrganicChemistry
UniversityofDebrecen
Debrecen,Hungary
ISSN1861-9282 ISSN1861-9290 (electronic)
TopicsinHeterocyclicChemistry
ISBN978-3-030-31941-0 ISBN978-3-030-31942-7 (eBook)
https://doi.org/10.1007/978-3-030-31942-7
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Preface
Spiro compounds that contain a bicyclic or tricyclic system to share a single atom
between two rings represent an increasing class of molecules of both natural and
synthetic origin. These compounds exhibit various biological activities and can be
used in materials science applications due to, e.g. photochromism and hole
transportingabilities.Theuniqueandwell-defined3Dstructureofspiroderivatives
makes them attractive targets in drug discovery, offering a deviation from the
traditional aromatic/heterocyclic “flatland” chemistry. The conformational con-
straints resulting from the spiro structure lend rigidity to these molecules, and this
may end up with a diminishing entropic penalty during binding to the biological
targets. The spirocyclic constructs can also meet the needs of discovering new
regionsofchemicalspaceandtherebyfacilitateuncoveringnewproperties,biolog-
icaleffectsaswellasmedicalandotherapplications.Inaddition,thesescaffoldsmay
beadvantageousinviewofpatentabilityaswell.Ontheotherhand,theconstruction
of spirocycles especially in terms of regio- and stereoselectivities poses a highly
provokingtasktothepreparativechemist.Duetotheaboveimportantandinterest-
ingpropertiesandthedemandingsyntheticchallenges,thespirocompoundsattract
more and more attention both in academia and industry that is reflected in the
appearanceoffivetosix thousands ofprimary publications andpatentsperannum
during the last decades. Furthermore, the utility of spirocyclic derivatives as com-
modities is demonstrated by marketed drugs, ophthalmic lenses and sunglasses,
auxiliary compounds in stereoselective syntheses, electronic displays, optical data
storagedevices,etc.Severalotherutilizationstowards,e.g.newmedications,chem-
icalbiosensing,controlledreleasedrugdelivery,molecularswitchesandsolarcells
areinadevelopmentalphase.
Carbohydrates are ubiquitous molecules in nature and participate in a vast
number of biological interactions. Their conjugates, including all kinds of primary
and secondary metabolic small molecules and also biomacromolecules, represent
valuabletoolsforglycobiologyresearchandalsoleadcompoundsfordrugdiscov-
ery.Whilemonosaccharides perse appear asheterocycles,theirnaturalconjugates
frequentlyexhibitspiro(hetero)cyclicderivatives,inmanycasesofhightherapeutic
v
vi Preface
relevance. Well-known carbohydrate-spiro-heterocycles are, e.g. the antifungal
papulacandins, the antibiotic orthosomycins, the herbicidal hydantocidin, each of
natural origin, and the synthetic tofogliflozin, the active ingredient of approved
antidiabeticmedications.
Monosaccharideswiththeirmultiplestereogeniccentresandvariousintramolec-
ular interactions involving the substituent groups on the sugar ring make the
formation of spirocycles on such a skeleton even more challenging in controlling
selectivities.Thus,theoutcomesofaparticularspirocyclizationmaywelldependon
the sugar moieties’ stereochemical and conformational peculiarities resulting in
differentproductsorproductratioswhenthesugarischanged.
Thisbookasawholeaswellasitsindividualchaptersintendstogiveaninsight
intotheworldofcarbohydrate-spiro-heterocyclesfromvariousperspectives.Inthe
introductorychapter,thecyclizationmethodologiestoformaspiro-fusedringatthe
anomericcarbonofpyranoidsugarsarecategorizedandaselectionispresentedby
PommierandVidal,who alsohighlightsomeimportantbiomedicalapplicationsof
suchcompounds.
Specific methods of spiro ring formation are emphasized in the next chapters.
Pellegrini-MoïseandRichardhighlight1,3-dipolarcycloadditionstoformcarbohy-
drate-derived spiro-isoxazolines and spiro-isoxazolidines and their transformations
into other interesting compounds. Martín and Suárez have compiled a plethora of
radical reactions to demonstrate their unique potential and versatility to achieve a
widerangeofspirocyclesonbothpyranoidandfuranoidsugarunits.Theformation
ofspiroketalsandrelatedlactonesbasedonunsaturatedmonosaccharidederivatives
suchasendo-andexo-glycalsissurveyedbySridhar.JosseandPostelsummarize
the uses of sugar-derived cyanohydrins and α-aminonitriles for the formation of
spirocyclesatringpositionsofcarbohydratesalsoinvolvingbiomedicallyoutstand-
ingderivatives.
Some important compound types are reviewed in the remaining chapters. The
multifacetedchemistryofspirocyclicnucleosidesisoverviewedbySoto,Rodríguez-
SollaandSoengasalsopointingouttheirbiologicalutility.Yamamotopresentsthe
syntheses and uses of phthalane spiro-C-glycosidic compounds including
papulacandins and tofogliflozin. Finally, a special and emerging type of
glycomimetics, the spiro-iminosugars, is surveyed by Hazelard, Hensienne, Behr
andCompain.
I greatly appreciate the meticulous work of the contributors, and I am also
indebted to those colleagues from all over the world who voluntarily reviewed the
manuscripts,therebyprovidinginvaluablehelpintheeditorialwork.
Debrecen,Hungary LászlóSomsák
March2019
Contents
AnomericSpiro-AnnulatedGlycopyranosides:AnOverview
ofSyntheticMethodologiesandBiologicalApplications. . . . . . . . . . . . . 1
MaximePommierandSébastienVidal
CycloadditionReactionsofSugar-BasedOlefins,NitronesandNitrile
Oxides:EnRoutetoSaccharidicSpiroisoxazoli(di)nes. . . . . . . . . . . . . . 27
NadiaPellegrini-MoïseandMylèneRichard
CarbohydrateSpiro-heterocyclesviaRadicalChemistry. . . . . . . . . . . . 51
AngelesMartínandErnestoSuárez
Carbohydrate-DerivedSpiroketalsandSpirocyclicLactones. . . . . . . . . 105
PeraliRamuSridhar
CyanohydrinsandAminocyanidesasKeyIntermediates
toVariousSpiroheterocyclicSugars. . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
SolenJosseandDenisPostel
RecentAdvancesintheChemistryandBiologyofSpirocyclic
Nucleosides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
MartínSoto,HumbertoRodríguez-Solla,andRaquelSoengas
SpiroketalPhthalaneC-Glycosides:SynthesisofPapulacandins
andSGLT2Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
YoshihikoYamamoto
SpiroIminosugars:StructuralDiversityandSyntheticStrategies. . . . . . 261
DamienHazelard,RaphaëlHensienne,Jean-BernardBehr,
andPhilippeCompain
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
vii
TopHeterocyclChem(2019)57:1–26
DOI:10.1007/7081_2019_33
#SpringerNatureSwitzerlandAG2019
Publishedonline:22August2019
Anomeric Spiro-Annulated
Glycopyranosides: An Overview
of Synthetic Methodologies and Biological
Applications
MaximePommierandSébastienVidal
Contents
1 Introduction................................................................................... 2
2 IntramolecularStrategiesTowardSpiro-AnnulatedCarbohydrates......................... 4
2.1 ThroughTwoPre-installedTethersandWithoutStereoselectiveOutcome(PathA)... 4
2.2 ThroughOnePre-installedTetherandwithStereoselectiveOutcome(PathB)...... 8
3 IntermolecularSyntheticStrategiesTowardSpiro-AnnulatedCarbohydrates.............. 10
3.1 StrategiesTowardSpiro-AnnulatedDerivativeswithThree-MemberedRings
(PathC)................................................................................. 10
3.2 StrategiesfromC-1gem-Di-ActivatedPyranosides................................... 11
3.3 ThroughaTetherandActivationattheAnomericPosition(PathD)................. 12
3.4 ThroughTwoTethers(PathE)......................................................... 13
4 StrategiesTowardBiologicallyActiveSpiro-BicyclicGlycopyranosides.................. 14
4.1 Papulacandin(PathB).................................................................. 14
4.2 Tofogliflozin(PathB).................................................................. 15
4.3 SynthesisofSpiro-BicyclicSystemsasPotentialGlycogenPhosphorylaseInhibitors.. 18
5 ConclusionandPerspectives................................................................. 22
References......................................................................................... 22
Abstract Organic chemistry developed a series of synthetic strategies toward
spiro-annulated carbohydrates as potential pharmaceutical drugs or developed new
organic synthetic methodologies. The present chapter gives a general overview of
the spiro-annulation of carbohydrates at the anomeric position. The main synthetic
strategies can be summarized in five paths. Intramolecular cyclizations can be
performed through two short tethers with their reactive ends generating the
M.PommierandS.Vidal(*)
InstitutdeChimieetBiochimieMoléculairesetSupramoléculaires(UMR5246),
UniversitéClaudeBernardLyon1andCNRS,BâtimentLederer,Villeurbanne,France
e-mail:[email protected]
2 M.PommierandS.Vidal
spirocycleorthroughasingletetherreactingattheanomericpositionforcyclization.
The three other strategies rely on intermolecular reactions with a portion of the
spirocycle only in the external substrate or also on the carbohydrate. Radical-
mediated cyclization and cycloaddition reactions are the main strategies toward
spiro-annulated carbohydrates. A special attention is paid to discussion of the
stereocontroloftheanomericconfigurationandalsotoyieldsinindustrialsyntheses
or biological activities of the molecules. A specific attention is devoted to
tofogliflozinandglycogenphosphorylaseinhibitorsbothusedasantihyperglycemic
drugsanddrugcandidates,respectively.
Keywords 1,3-Dipolarcycloaddition·Cycloaddition·Glycogenphosphorylase·
Hydrogenatomtransfer(HAT)·Medicinalchemistry·Radicalcyclization·
Ring-closingmetathesis·SGLT2·Spiroketal·Spiro-lactam·Type2diabetes
1 Introduction
Carbohydrates areamajorclass ofnaturalproductswith biological implicationsin
bacterial or viral infections, cancer signaling or metastasis, and inflammation.
Chemists have intensively investigated the synthesis of not only oligosaccharides
forapplicationsinvaccinesbutalsomimeticsofmonosaccharidesforthedesignof
potentialdrugsorinamedicinal chemistryapproach.Theseeffortshavegenerated
literatureontheprotectinggroupstrategies[1]andalsoglycosylationmethodologies
[2,3] for theoptimalsyntheses of suchnaturaloligosaccharides or glycomimetics.
Spiro-annulatedcarbohydratesarethefocusofinvestigationstodesignpharmaceu-
tical drugs or to develop new synthetic approaches for their preparation. Natural
productssuchaspapulacandinortherecentlyapprovedsynthetictofogliflozinasan
antihyperglycemic drug used for the treatment of type 2 diabetes are some leading
examplesinthisseries(Fig.1).
Fig.1 Structureof Me
papulacandinDand Me OHHO
tofogliflozin Me HO O OH
O
HO
O
OH O
Papulacandin D
Et
OH
HO O
HO
HO
O
Tofogliflozin
