carbocyclization of carbohydrates to hydroxylated …...to give the cyclohexene motif, the protected...
TRANSCRIPT
No.178
2
No.178
O
O O
OCH2PhXO
HOHO
OH
OH
HO
D-Mannose
1 X = OH2 X = OTs3 X = I4 X = OSO2CF3
O
O O
OR
(MeO)2P CO2tBu
O
5 steps
~60%overall yield
5 R = CH2Ph6 R = H
(MeO)2P CO2tBu
O
Na+ -
DMF, 15-crown- 5
CO2tBu
OO
HOCO2H
HO
OH
HO aq. TFA
Shikimic acid
~39%overall yield NaH,
THF
7
Scheme 1. Synthesis of shikimic acid
Thisreviewarticledescribesourresearcheffortsonfindingashort,facile,andefficientwayoftransformingcarbohydratesinto hydroxylated carbocycles over a period of about 30 years. There are excellent reviews on the topic published elsewhere.1
The storybeginswhen Iwas apostdoctoral fellowatOxfordworkingwithProfessorGeorgeFleetin1983.Weweretrying tosynthesizeshikimicacid fromD-mannoseusinganintramolecularaldolcondensationoraWittig-typealkenationas thekeystep. Installingaphosphono-acetatemoietyat theC-5ofthebenzylfuranosideintermediate1toformtheWittig–Horner–Emmonsprecursormetwithdifficulty(Scheme1).2
Simple SN2 displacement reactions in carbohydrates are knowntobesluggish/difficultduetothehighconcentrationofoxygenfunctions (electronrich). Thus thederivedstandardelectrophiles, 5-tosylate 2 and 5-iodide 3 were found to be inert towardssubstitution. Wethenattempted touse the5-triflate4 as a reactive leavinggroup (thiswasnewat that time).Gratifyingly, thealkylationproceededsmoothly togive theHorner–Wadsworth–Emmons(HWE)alkenationprecursorinagoodyield. Subsequentunmaskingthealdehydefunctionin5 byhydrogenolysisaffordedlactol6 that was treated with base togive thecyclohexenemotif, theprotectedshikimicacid7. Acidcatalysedremovalof theblockinggroupsin7 furnished shikimic acid in an excellent overall yield.2
Abstract:Carbohydrates, inexpensiveandrich instereochemistry,arenature’sgifts to thesyntheticorganicchemists.Wehavebeenconductingresearchonthecarbocyclizationofcarbohydratesformanyyears, i.e. theconversion of simple, readily available monosaccharides into hydroxylated cycloalkanes and cycloalkenes with pharmaceutical potential. Several key reactions are presented in this Article to illustrate such facile transformation namely [π4s+π2s] cycloaddition - intramolecular nitrone-alkene and nitrile oxide-alkene cycloadditions, intramoleculardirectaldolreactionandintramolecularHorner–Wadsworth–Emmonsolefination.Theseprotocolsprovide facile entries to 6 and 7-membered hydroxylated carbocycles in enantiomerically pure forms which then couldbefurtherelaboratedintotargetmolecules.Examplesincludingcalystegines,tropanealkaloid,cyclohexanylandcyclohexenylgabosines,cycloheptanones,valiolamine,validoxylamineG,pseudo-acarviosin,andaSGLT2inhibitor are presented.
Keywords:carbohydrates,naturalproducts,organicsynthesis,pericyclicreactions,hydroxylatedcarbocycles
Research ArticleResearch Article
Carbocyclization of Carbohydrates to Hydroxylated Cycloalka(e)nes
TonyK.M.Shing
Department of Chemistry, Faculty of Science and Technology, Keio UniversityEmail: [email protected]
No.178
3
Up todate, this intramolecularHWEalkenation is stilloneofthemostpowerfulstrategiesforthecarbocyclizationofsugarmolecules.AnotableexampleofusingthisstrategywasdemonstratedbyFangandco-workers3 tosynthesizeanti-viralagentTamiflu® 12anditsmorepotentphosphonateanalog13 in asimilarmanner(Scheme2).*Tamiflu®isaregisteredtrademarkofF.Hoffmann-LaRoche,Ltd.
The reasons for researching on carbocyclization ofcarbohydratesareattributedto thefact thatmanybiologicallyactivemolecules are hydroxylated cycloalkanes/alkenes.Carbohydratesareobviousstartingmaterialsthatofferthemostfacileandeconomicalwaytoapproachthesehighlyoxygenatedcarbocycleswithdefinedstereochemistry.
Some hydroxlated cyclohexanes and cyclohexene are listedinFigure1.Theydisplayawideplethoraofbioactivitiesincludingantibiotic,antitumor,antiviral,glycosidaseinhibitoryactivities.
Calystegines,4displayedspecificglycosidase inhibition, areagroupofbicyclicheterocycleswhichare inequilibriumwith the open chain form, a hydroxylated gamma-aminocycloheptanone that are potentially accessible from carbohydrates (Figure2).
Gabosinesareagroupofhydroxylatedcyclohexanones/cyclohexenones that display antibiotic, anticancer, and DNA bindingproperties(Figure3).5 All these compounds should in theorybeapproachablefromsugars,buthowcouldweeffectthecarbocyclizationefficiently?
NH
OHHO
HO
OHHOOH
OH
HO
O OH
OHHO
AO-128 18Voglibose
O
O OH
OHHO
O
EtO
O
NHAcH3N
O
H2PO4-
KD16-U1 14 COTC 15
Tamiflu® 12
NH2
OHHO
HO
OHHO
Valiolamine 19
EtO
Cl OH
OHHO
Pericosine A 16
OEtO
MeO OH
OHHO
Pericosine B 17
O
OH
OHHO
HO
HO
α-D-Glucopyranose 20
Calystegine B5
O
NH2
HO
HOCalystegine A6
NHHO
HO
OH
O
NH2
HOOH
R = H Calystegine C1
NHO
HOHO
OHOH
O
NHRHO
OHHO
HO
NHHO
OH OHOH
OH
R
R = CH3 N-methyl calystegine C1
D-Xylose
O
AcN O
OCH2Ph
(MeO)2P EO
8 E = CO2Et9 E = PO(OEt)2
E
AcNO
HO
E
AcHNO
H3N
10 E = CO2Et11 E = PO(OEt)2
12 E = CO2Et (Tamiflu )
13 E = PO(OEt)2
H2PO4-
Figure 1. Bioactive hydroxylated cyclohexanes and cyclohexenes
Figure 2. Structuresofsomecalystegines
Scheme 2. Synthesis of Tamiflu®anditsphosphonateanalog
No.178 No.178
4
Towardsthatend,wehavebeeninvestigatingthefollowingstrategiesforthecarbocyclizationofsugars:
1.CarbocyclizationofCarbohydratesvia anIntramolecularNitrone-AlkeneCycloaddition(INAC)
2.CarbocyclizationofCarbohydratesvia anIntramolecularNitrileOxide-AlkeneCycloaddition(INOAC)
3.CarbocyclizationofCarbohydratesvia anIntramolecularDirectAldolAdditionofSugarDiketone
4.CarbocyclizationofCarbohydratesvia anIntramolecularHorner-Wadsworth-Emmons(HWE)Olefination
From1984, I startedmy independent researchcareerattheUniversityofManchester andbegan to investigate theconstructionofcarbocyclesusinganINACreactionasthekeystep.
1. Carbocyclization of Carbohydrates via an Intramolecular Nitrone-Alkene Cycloaddition (INAC)
2,3-O-IsopropylideneD-ribose 23 underwent a chelation controlledGrignardvinylation togive triol24 (Scheme3).Glycolcleavageoxidationofthevicinaldiolin24 affoded lactol 25whichonheatingwithN-methyl hydroxylamine furnished a hydroxylated cyclopentane 27 smoothly. This is an extremely short approach towards 5-membered carbocycles and its application to the syntheses of carbocyclic nucleosides should have received more attention.6
On the other hand, chelation controlled vinylation of diacetone mannose 28gaveallylalcohol29 stereoselectively which was protected as benzyl ether 30 (Scheme 4).Regioselectivemildacidhydrolysisof the terminalacetonidewas feasible as the O-8was the leasthinderedand thereforeprotonatedfirst. Theresultantdiol31 was oxidatively cleaved to afford aldehyde 32 which was reacted with N-methyl hydroxylaminetogivenitrone33.INACoccurredsmoothlyonheatingtogivecyclohexane34ingoodyield.Inbothcases,thenewC–Nbondisanti to the O-2stereochemistryandtheringfusion is cis.6
OMeHO
HOOH
OMeHO
HOOH
OHO
HOOH
OR
OHO
HOOH
OR
OMeHO
HOOH
OHHO
OHHO
(–)-Gabosine A (–)-Gabosine B R = H, Gabosine C 14R = crotonyl, 15
R = H, (+)-Gabosine E R = Ac, (+)-Gabosine D
(+)-Gabosine F R = H, (–)-Gabosine I R = Ac, Gabosine G
Gabosine H Gabosine J
OMeHO
HOOH
OMeHO
HOOH
Gabosine K (–)-Gabosine O(–)-Gabosine N(–)-Gabosine L
OR
O
OH
HO
HO Me
OHO
OHHO
OH
O
OHHO
HO
Me
OHO
HO
HO
OAc
O
O O
OHHO
O O
OH
O O
HO
HO OH
THF, 72%
O
O O
HONaIO4
aq. MeOH, 90%
OMeN
O O
OH
O-
MeN+
NHMeOH
aq.EtOH
94%
2324 25
27 26
MgBr
Figure 3. Gabosinefamily
Scheme 3. Synthesisofafunctionalizedcyclopentane27 from ribose
No.178
5
Wehadmoreinterests in thisINACreactionbecausewereasoned that it could be controlled to provide 7-membered carbocycles. Whenasugarmoleculewaselaboratedtohaveaterminal alkene, on reaction with N-alkyl hydroxylamine, there wouldbetwopossiblemodesofINACcyclization, the exo or the endomode(Scheme5),whichleadstoeitherafusedorabridged isoxazolidine, respectively.7 To be specific, a hept-6-enose would provide either a fused bicyclo[4.3.0] system, i.e. a cyclohexane skeleton from an exo-modeora bridgedbicyclo[4.2.1] system, i.e. a cycloheptane skeleton from an endo-modeINACcyclization. Wewereparticularlyintriguedby the potential formation of 7-membered carbocycles as there arefewsyntheticstrategiestowardscycloheptaneswhereasthesynthetic methods for the construction of 5- and 6-membered carbocycles are plentiful.
Werealisedthat theformationofacyclohexaneskeletonvia the exo-modeofcyclizationofhept-6-enose is theusualregioselectivityoutcomewithconventionalprotectinggroupslikebenzylether, silylether, acetonide,andestersetc. Forexamples, nitrone 35 and 36, both with a cis-diol acetonide protectinggroupgavecyclohexaneringsinhighyields(Scheme6).8 The stereochemistry of 4-OH apparently had no effect on theregioselectivity.
We reasoned that themode of cyclizationmight becontrolledby theblockinggroupsas theyaffect theorbitaloverlap between the nitrone and the alkene. Thus we investigatedtheeffectof trans-diacetalblockinggroupontheregioselectivityofhept-6-enose. Epimericnitrones37 and 38 were readily prepared from D-arabinoseinvolvingglycosidationwithbenzylalcohol,diacetalisation,debenzylation,Grignard
N+-O
NO
R N+
-OR R N
OR
fused bicyclo [X.3.0] bridged bicyclo [X.2.1]
exo mode of cyclization endo mode of cyclization
N+-O
NO
RN+
-OR R N
OR
fused bicyclo [4.3.0] bridged bicyclo [4.2.1]
R' R'
R' R'
R' R'
R' R'
( )x ( )x ( )x( )x
N+-O
RO RNHOH R-alkyl groupe.g. Bn, Mesugar
aldehyde nitrone
Scheme 5. INACmodeofcyclization
HOOHO O
OBn OBnO
MeN
OO
OBn
BnO
O-
MeN
OO
OBn
BnO
+
O OH
O O
OO
OO O O
OH OH
OO O O
OBn OBn
aq. AcOH, 64%BnBr, NaH
O
OO
OBn
BnO
65% overall from 32
aq. MeOH
2829 30
31 32 3334
THF, 93% THF, 79%
MeNHOH
aq. EtOH
MgBr
NaIO4
92%
OO
ON
OH
Me
OO
OH
ONMe 1
23
12 3
OO
ON
OH
Bn
OO
OH
ONBn
94%
12
3
1
23
35 36
Scheme 4.Synthesisofafunctionalizedcyclohexane34 from mannose
Scheme 6. INACofhept-6-enoseswithacis-acetonide
No.178
6
No.178
allylation,glycolcleavageoxidationandreactionwith N-methyl hydroxylamine.Interestingly,nitrones37 and 38 with a trans-diacetalblockinggroup(thediolmoietyis trans)afforded endo-modeofcyclizationproducts41, 44, 45, i.e., cycloheptane rings, for thefirst time(Scheme7). Anothernotablefeatureof this reaction is that a trans-fused bicyclo[4.3.0] system, i.e. cyclohexane 40 and 43 were formed. The lower yield of cis-fused 42 andhigheryieldof trans-fused 43 is probably attributed to the 1,3 diaxial interaction between 4-OH and the 6-hydroxymethyl in 42, this steric interaction is absent in the cis-cycloadduct 39. Therigidityof thediacetal ringrequires2-O and 3-O in the trans-diequatorialdispositions, thus4-OHand the 6-hydroxymethyl in 42 must be axial.8
We reasoned that cycloheptane ringmight bemoreaccommodating than6-membered ringsas faras ringstrainis concerned. We thereforewent on to study the effectof an acetonide with a trans-diol blocking group on theregioselectivity of nitrone cycloaddition of hept-6-enose(Scheme8). Nitrones46 and 47 with an acetonide of trans-2,3-diol provided endo-cycloadducts 48 and 49 as the major productsforthefirsttime.9
Hept-6-enose nitrones 50 and 51 with a 3,4-trans-acetonide were even more remarkable as only the endo-mode cycloheptaneswereharvestedingoodyields(Scheme9).10
ON
OO
Me
OH
ON
OO
Me
OH OO
NOMe
OH
+
13%81%
1
23
12
3
12
3
ON
OO
Me
OH
ON
OO
Me
OH OO
NOMe
OH
+
31% 63%
1
23
12
3
12
3
46
47
48
49
OO
N OMe
HOO
OHO
NMeO
23 4
1 12
3 4
OO
N OMe
HO
12
3 4+
85% 8%
OO
NBnO
OBz
BnOO
O
NOBn
OBz
BnO
+
OO
NOBn
OBz
BnO
56% 29%
1
23 4
12
3 412
3 4
50
51
ON
OO
Me
OMe
MeOOH
ON
OO
Me
OMe
MeOOH
ON
OO
Me
OMe
MeOOH O
O
NOMe
OH
OMe
MeO
64% 18% 16%
+ +
1
23
12
3
12
3
12
3
ON
OO
Me
OMe
MeOOH
ON
OO
Me
OMe
MeOOH
ON
OO
Me
OMe
MeOOH O
O
NOMe
OH
OMe
MeO
27% 35% 17%
+ +O
O
NOMe
OH
OMe
MeO
+
21%
1
23
12
3
12
3
12
3
12
3
6
4
37
38
39 40 41
42 43 44 45
Scheme 8. INACofhept-6-enoseswitha2,3-trans-acetonide
Scheme 9. INACofhept-6-enoseswitha3,4-trans-acetonide
Scheme 7. INACofhept-6-enoseswithatrans-diacetal
No.178
7
Wewerewonderingif thestereochemistryoftheC-2/C-5hydroxylgroupsmightaffect theregioselectivityoftheINACreactions. Wethusconstructedahept-6-enosenitrone60 with only a 3,4-trans-acetonide from L-tartaricacidusingstandardreactions (Scheme10). Only a cycloheptane ring61 was obtained,therebyconfirmingthatthe endo-modeofcyclizationwas controlled by the trans-acetonidering.11
Since we have established that 7-membered cycloheptanes can be accessed via a trans-acetonide directed endo-selective INAC reactionsofhept-6-enoses,we setout to synthesizecalystegineanalogs. In thisway,D-xylose was transformed into cycloheptanes 63, 64, 65 with a 3,4-trans-acetonide (Scheme11). Debenzoylation afforded the correspondingalcohols in which 66 and 68were oxidized to the sameketone 69. Acidic deacetonation of 69 followedbyglobalhydrogenolysis furnished (S)-3-hydroxy-calystegineB5 71.10 We found that tert-butanolwas a good solvent forhydrogenolysisofa N-benzylgroupasnosideproductsfrom N-alkylation was possible.
OO
HO OH
OO
MeO OMe
OO
MeO OMeAcCl, MeOH
reflux Dean & Stark trap88% from 52
conc. H3PO4, 3-pentanone
L-Tartaric acid (52) 53 54
O OHO OH HO OH
LiAlH4
THF, reflu x
55
O O
HO OH I2, PPh3, Im
toluene, rt77%
THF, –78 °C to –30 °C73%
56 57
O O
CuMgI • MgBr22
O O
I I
O O
HO
HO
58
5 mol% OsO4, NMO
aq. acetone 45%
BnNHOH
MeCN, reflux86% from 58
59
NaIO4, silica gel
CH2Cl2, rt O O
H
O
N O
O O
Bn
61
N O
HO OH
Bn
TFA, H2O
CH2Cl2, rt100%
62
H2N OH
HO OH63
H2, Pd/C
t-BuOH/H2O (v/v=5:1)rt, 94%
O O
N OBn
60
endo-modeINAC
(10 steps, 27% overall yield from L-tartaric acid)
3 4
99%
Scheme 10. INACofhept-6-enosewithonlya3,4-trans-acetonide
No.178
8
No.178
On the other hand, D-ribose was converted into aldehyde 72 which underwent trans-acetonide directed endo-selective INACreaction togivecycloheptane73 in an excellent yield (Scheme12). Acidhydrolysisof theacetonideringproduced
the diol 74whichunderwentstericcontrolledregio-selectiveoxidation of the less hindered alcohol to give ketone75. Hydrogenolysisofthe N–ObondaffordedaB-typecalystegine76.10
OHCO O
OBn MeNO
O OBnO
MeNHOHD-Ribose
5 steps
MeNO
HO OHBnO100%97%56%
Ac2ODMSO
TFA
MeN O
HO OBnO
75
HO OHO
MeHNOH
NMeHO
HO
HO
HO
10% Pd/C, H2, t-BuOH/H2O
(v/v=5:1), rt, 48h, 87%
76 B-type calystegine analog
7273 74
Scheme 12. SynthesisofaB-typecalystegineanalog
68
N O
BnO
Bn
O O
OH
K2CO3, MeOH/CH2Cl2 rt, 24 h, 91%
66
N O
BnO
Bn
O O
OH
K2CO3, MeOH/CH2Cl2 rt, 8 h, 100%
67
N O
BnO
Bn
O O
OH
63 (14%)
N O
BnO
Bn
O O
OBz
64 (7%)
N O
BnO
Bn
O O
OBz
65 (14%)
N O
BnO
Bn
O O
OBz+O
OHHO OH
OH
D-Xylose
10 steps+
K2CO3, MeOH/CH2Cl2 rt, 6 h, 100%
66
N O
BnO
Bn
O O
OH
68
N O
BnO
Bn
O O
OH
69
N O
BnO
Bn
O O
OIBX, DMSO/CH2Cl2
(v/v=1:1), rt, 100%
IBX, DMSO/CH2Cl2
(v/v=1:1), rt, 100%
69
N O
BnO
Bn
O O
OTFA, H2O
CH2Cl2, rt
70
N O
BnO
Bn
HO OH
O10% Pd/C, H2
t-BuOH, rt, 92%
NHHO
OHOH
O
NH2HO
HOOH
HO OH
OH
71 (S)-3-Hydroxy-calystegine B5
NHHO
OHOH
OH
Calystegine B5
O
NH2HO
HOOH
412
3 5
67
Scheme 11. SynthesisofacalystegineB5analog
No.178
9
Thenweinvestigatedthisendo-selectiveINACapproachtowards syntheses of tropane alkaloid 90andanalogs.
(A) Strategy towards tropane alkaloid 1: INAC of a Nitrone with a 2,3-cis-Isopropylidene as Blocking Group and an a,b-Unsaturated Ester as Dipolarophile
Since the alkene moiety in 77 is an electrophilic alkene whereas the alkenes used in our INAC cyclizationmodestudieswere simplenucleophilic alkenes,wewerehopingthat theelectrophilicalkeneof theenoategroup in77mightcause an endo-selectiveINACreactionattributabletoHOMO–LUMOreasons (Scheme13). Thisproposalwassupportedby a precedent12 that in the intermolecular nitrone-alkene cycloaddition of a,b-unsaturated ester 82, and nitrone 81, the newC–Owas installedon theb-carbon in cycloadducts 83 and in 84(Scheme14).IfthiswereappliedtoourINACcase,the endo-modecyclizationwouldhavetakenplace. Wewereexcited with this precedent and therefore proceeded with the synthesis.
Toourdisappointment, theINACofnitrone85 produced only exo-mode cycloadducts 86 and 87 , 6-membered carbocycles. Hence it appears that steric control is more important thanelectroniccontrol for theregioselectivity(exo versus endo)ofINACreactionsofhept-6-enoses(Scheme15).11
(B) Strategy towards tropane alkaloid 2: INAC of a Nitrone with a 3,4-trans-Isopropylidene as Blocking Group and an a,b-Unsaturated Ester as Dipolarophile
Since we had shown that 3,4-trans-acetonide would direct an endo-selectivemodeofcyclization,wedevisedasyntheticroute towards tropane alkaloid 90 based on this key step as summarised in Scheme 16.
OHH
H
+CO2Me
OHH
HN O
CO2Me
Me
NO
Me
OHH
HN O
CO2Me
Me+
xylene
140 °Cαβ
αβ
αβ
8182 83 84
exo-modeINAC
endo-modeINAC 4
12
3
1
23
OOHO
NMe
OCO2Et
4
O NMe
O
O
HO
MeN
O
O
CO2EtHO
EtO2C
NO
O O
Me
H
H
CO2Et
HO 123
4
?
?77
78
79
80
O
O O
OHEtO2C MeNHOH • HCl, py
O O
NO
Me
CO2Et
HO
(60%)
exo-modeINAC
H
H
O O
NO
MeHO
CO2Et
EtOH, reflux, 2 h
(11%)
+NO
O O
Me
H
H
CO2Et
HO
85
86 87
Scheme 14. Intermolecularcycloadditionofnitrone81 and enoate 82
Scheme 13. Orbital controlled synthetic plan towards tropane alkaloid
Scheme 15. INACofenoatewithacis-acetonide
No.178
10
No.178
Capitalising fromour studies that 3,4-trans-acetonide wouldproducecycloheptaneringonINACreactionsofhept-6-enoses, we proceeded to prepare the nitrone 97 from ribose.13 The known allyl alcohol 91 was readily obtained from D-ribose via asteric-controlledallylation(Scheme17).Thermodynamicacetonation of 91 formed the7,8-O-isopropylidene first as theprimary8-alcoholwas themost reactiveofall. Thenanacetonide was formed between O-4,5 instead of O-5,6 because thesubstituentson theacetonidering92 were trans to each other. The diacetonide 92 was then transformed into diol 95without incident. Glycolcleavageoxidationof95 with
silicasupportedNaIO4 furnished aldehyde 96 smoothly. This solid-phaseNaIO4 reagent14 ishighly recommendedas theoperation is very simple and the aldehyde harvested is usually un-hydrated. INACreactionof97 did produce the desired cycloheptane derivative 98 as the major product.13
As the cycloheptane skeleton was installed correctly, cycloadduct 98 was converted into natural tropane alkaloid 90 anditsanalogs100–104asshowninFigure4.13
OHO
HO OH
OH
D-Ribose
OH
OH
OH
OHHO
64% from D-Ribose
OH
O O
OO
91 92
anhydrous CuSO4
acetoneIn, allyl bromide
EtOH/H2O
OBn
O O
OO
93
BnBr, NaHcat. nBu4NI
THF, 98%
OBn
O O
OO
CO2Me
CO2MeGrubbs catalyst II
CH2Cl2, 95%
94
80% AcOH
rt, 73%
OBn
O O
HOHO
CO2Me
95
NaIO4, silica gel
CH2Cl2, rt
OBn
O O
H CO2Me
O
96
99
+
ON
O O
CO2Me
BnOH H
Me
O O
BnO
NO
MeCO2Me
97
INAC
O O
ONMe
BnO
98
CO2Me
(endo-cycloadduct) (exo-cycloadduct)
toluene, reflux
NHMeOH
75%
15 1
O O
ONMe
BnO
O O
BnO
NO
MeCO2Me
1
23 4
12
3 4 NMe
CO2MeOBz
Tropane alkaloid 90
O O
ON CO2Me
HH
Me
BnO1
23 4
endo-modeINAC
exo-modeINAC
CO2Me
88
89
Scheme 17. INACsyntheticroutetowardstropanealkaloid
Scheme 16. Steric controlled synthetic plan towards tropane alkaloid 90
No.178
11
2. Carbocyclization of Carbohydrates via an Intramolecular Nitr i le Oxide-Alkene Cycloaddition (INOAC)
Theuseofchloramine-T in theconversionofene-sugaroximeintoanitrileoxideanditssubsequentINOACreactionis known.15 ThiscycloadditionshowninScheme18canonlybe exo-mode as the endo-modeofcyclizationwouldproducean impossibleC=Nbondat thebridgeheadposition(Bredt’srule).16
Common chemicals for the transformation of oxime in to n i t r i le ox ide inc lude NaOCl , NaOCl/NEt 3 and N-chorosuccinimde/NEt3.16 Under the basic conditions,
the freehydroxylgroup innitrile oxide105 would attack the nitrile carbon to give oximolactone106 and failed to produceacarbocycle. Thehydroxygroupsof thesugarhaveto be protected in order to achieve satisfactory yields. Thus, providingamildlyacidicenvironmentfortheINOACreactionsiscrucial inachievingafruitfulcarbocyclizationwithout theformation of oximolactone.
Wefoundthataddingflashchromatographysilicagel to“buffer” the reaction medium dramatically increased the yield ofthechloramine-TmediatedINOACreactionfrom62to94%(Scheme20).17
Nitrile oxide 105
O
O O
NHO
Oximolactone 106
O O
NO
HO
aq NaOClor NCS, Et3N
OO
OH
N
MeO
OMe
HO
OO
OH
MeO
OMe
ON
107 108 (62%)
Chloramine-T
EtOH, rt
EtOH, rt108 (94%)Chloramine-T, silica gel
NOH
ONChloramine-T N
O*
Oxime Nitrile oxide Isoxazoline
exo
only
Scheme 19. Formationofoximolactoneunderbasicconditions
Scheme 20. INOACwithandwithoutsilicagel
Scheme 18. Intramolecularnitrileoxide-alkenecycloaddition(INOAC)
OBzCO2Me
BnO NMe
Cl
100(12 steps, 23% overall yield)
OBzCO2Me
HO NMe
OBzCO2Me
MsO NMe
103(14 steps, 16% overall yield)
101(13 steps, 17% overall yield)
OBzCO2Me
Cl NMe
102(14 steps, 15% overall yield)
OBzCO2Me
I NMe
104(15 steps, 12% overall yield)
OBzCO2Me
NMe
Tropane alkaloid 90(15 steps, 12% overall yield)
Figure 4. Tropane alkaloid 90anditsanalogs
No.178
12
No.178
Towards the construction of 5-membered carbocycles, similar improvement in reaction yields were observed and examplesareshown inScheme21. It is interesting tonotethatotheracidicconditionsattemptedincludingtheadditionofaceticacid,benzoicacid,acetatebufferorphosphatebufferdidnotcausetheINOACtooccur.
ThesilicagelmediatedINOACreactionswerecompatiblewithsubstratescontainingunprotectedhydroxylgroups, thusreducingmasking/unmaskingstepsandrenderingasynthesisshorter.17
Wehaveappliedthismethodologyto theconstructionofgabosineOandF.18 Mannose was transformed readily into oxime 114withafreehydroxylgroup(Scheme22).INOACof114occurredsmoothly togivea6-memberedcarbocycle115 whichwashydrogenolysed,dehydrated,andthenhydrogenatedfrom the less hindered side to form ketone 118. Acidic hydrolysis of the acetonide in 118yieldedthetargetmoleculegabosineO.18
On the other hand, L-arabinose was transformed into oxime 119withafreehydroxylgroup.INOACreactionof120 furnished the 6-membered carbocycle in an excellent yield with thenewC–Cbondequatoriallyinstalled. StandardconversionaffordedthetargetmoleculegabosineF(Scheme23).
O O
OH
ON
110 (53%)
+
O
O O
HO
109
O
O O
NHO
106 (33%)
1) NH2OH
2) Chloramine-T, EtOH, rt
1) NH2OH
2) Chloramine-T, silica gel, EtOH, rt
NHO
OHHO
OHONHO
OHHO
112 (51%)111
Chloramine-T
EtOH, rt
110 (87%)
112 (87%)Chloramine-T, silica gel
EtOH, rt
106 (78%)2) NaOCl (aq), CH2Cl2, 0 °C
1) NH2OH
O
HOOH
OH
OHHO
MgBr
O O
OO
OHOH
O O
HONHO
OH
ON
O O
D-Mannose
1) acetone, H+, 92%
2)
THF, 83%
1) H5IO6, Et2O, 79%
2) NH2OH, MeOH 100%
Chloramine-Tsilica gel, EtOH
79%, α:β = 4.6:1
113 114
115
OHO
O O
118
OHO
HO OH
Gabosine O
89% from 116
H2, Raney Ni, AcOH
97%, α:β = 6:1
OHO
O O
HO
Martin’s sulfurane H2, Raney Ni aq.TFA
116
OHO
O O
117
Scheme 21. INOACwithandwithoutsilicagel
Scheme 22. SynthesisofgabosineO
No.178
13
3. Carbocyclization of Carbohydrates via an Intramolecular Direct Aldol Addition of Sugar Diketone
First of all,we startedour investigationonD-glucosesincevoglibose18 and valiolamine 19 are obvious synthetic targets.GlycosidationofD-glucosewithallylalcoholandthen
diacetalizationproduced2,3-124 and 3,4-diacetals 123 which were readily separable upon acetonation to the 4,6-acetonide 126.19 Palladiumcatalyseddeallylationofglycoside126gavelactol 127whichunderwentGrignardmethyladditionfollowedbyPDCoxidationaffordedthe2,6-diketone129.Intramolecularaldol addition reactions of 129 were carried out under various basic conditions and the best results are shown in Table 1.
OHO OH
HO
D-Glucose
122 123 124
OHO OAll
HO OHO OAll
HO
O OMeO OMe
2,3-butadioneCH(OMe)3MeOH
acetone
OO OAll
HO
O OHOMe
MeO
HO
HO
OH
OH
+
125 (40%) 126 (43%)
OO OAll
O
O OMeO OMe
OO OAll
HO
O OHOMe
MeO+
OH OMeMeO
127 128
OO OH
O
O OMeO OMe
MeMgBrTHF
OHO
OH
O
O OMeO OMe
95%
92%
82%
K2CO3, MeOH
PDC, 3Å MSCH2Cl2
Pd(PPh3)4
126
OO OAll
O
O OMeO OMe
129
OO
O
O
O OMeO OMe
O
O
O OMeO OMe
O
OH
Intramolecular direct aldol reaction
BF3 • OEt2
O
HOOH
OH
OH
silica gel, EtOH, 94%
N
HO
OOMe
MeO
HOHO
Chloramine-T
OO
ON
OH
OMe
MeOL-Arabinose
H2, Raney Ni, AcOH
OO
O
OHMeO
OMe
OH
121
HOOH
OH
O
Gabosine F
90%
119 120
1) AcCl
2) Et3N3) H2, Raney Ni
6 steps
Scheme 24. Preparationof2,6-diketone129 from D-glucose
Scheme 23. SynthesisofgabosineF
No.178
14
No.178
The stereo-selective formation of a particular aldol product can be controlled by either L-proline, strongorweakaminebase. It isnoteworthy thatall thedirectaldol reactionsarenot reversible. The resistance towards a retro-aldol reaction is probably attributable to steric reasons.
The preparation of mannose diketone 135 was executed in asimilarmanner(Scheme25).Disappointingly,allstrongandweakbasicconditionsfailedtogenerateanaldolproductwith
the exception of L-proline, which provided aldol 136 as the sole cyclohexanonein60%yield.19
We have also investigated an intramolecular directaldolizationof2,7-diketones, insearchforasyntheticavenuetowards hydroxylated cycloheptanones. The 2,7-diketones were prepared from D-ribose or D-mannoseusingstandardreactionsandtheresultsaresummarizedinScheme26.20
OHO
HO OH
OH
HO OO OH
O
O O
OHO
OH
O
O O
OO
O
O
O O
1) 2-methoxypropene p-TsOH, DMF
2) Ac2O, pyridine
OO OAc
O
O O
K2CO3MeOH
MeMgBrTHF
1) (COCl)2, DMSO 3Å MS, CH2Cl2
2) DIPEA
D-Mannose
61%93%
88%75%
O O
O
O O
OH
L-proline
DMSO60%
135 136
133134
O
HO OH
OHHO L-prolineDMSO, 24 h
92% O O
BnO
OOHTBSO
O O
BnO
OOTBSO
D-Ribose
O
HO OH
OHHO
OH
O O
OBnBnO
OOHTBSO
O O
OBnBnO
OOTBSO
87%
L-prolineDMSO, 21d
D-Mannose
O
HO OH
OHHO
O O
OBnO
TBSO
O
O
O OBn
TBSO
O
OH
O
O OBn
OTBSOOH
O
O OBn
TBSO
O
OH
L-prolineDMSO, 3d
91%
+ +
D-Ribose
139 (55%) 140 (19%) 141 (17%)
137
138
129
OO
O
O
O OMeO OMe
130
O
O
O OMeO OMe
O
OH
131
O
O
O OMeO OMe
O
OH
132
O
O
O OMeO OMe
O
OH
+ +
Scheme 25. Preparationofaldol136 from D-mannose
Scheme 26. Summaryofdirectaldolizationof2,7-diketonesfromriboseandmannose
Entry ConditionsResults
130 131 132
1 L-Proline (0.3 eq), DMSO 82% 8% 2%
2 KHMDS (1 eq), Toluene, -78 °C – 75% –
3 Et3N (1.5 eq), CH2Cl2 – – 95%
Table 1. Summaryofdirectaldolizationconditionsof2,6-diketone129
No.178
15
Application of the versatile intramolecular direct aldolization strategy to synthesiswasdemonstratedby thefollowingexamples.
3a. Synthesis of Valiolamine and Voglibose (AO128)
D-Glucosewas transformed smoothly into aldol131 as stated above. Oximation of the ketone moiety in 131 followed by hydrogenation/hydrogenolysis furnishedamine 142. Acidic removal of the acetals in 142 provided vailolamine 19 which, reportedly, could be converted in to the an t i -d iabe t ic agent vogl ibose (AO128) 18 (Scheme27).19
3b. Synthesis of Pseudo-Acarviosin
Methyl acarviosin 143 was obtained from the natural anti-diabeticagent,acarbose,byacidicmethanolysis(Figure5).Asmethylacarviosinisastrongera-amylase inhibitor, we wanted toreplacethesugarmoietyin143 with a cyclohexane to render thecompoundmorestabilityinacidconditions. Insearchforan improvedanti-diabeticdrug,weproceeded to synthesizepseudo-acarviosin 144forbiologicalscreening.
Retrosythesisofpseudo-acarviosin144 via a palladium catalysedallylic substitutionwouldgive two fragments, anallylic chloride 145 and a cyclohexanyl amine 146. Chloride 145 would be accessed from D-glucosevia adirectaldolstrategywhile the amine 146 should be approached from L-arabinose throughanINACreaction.21
NH
OHHO
HO
HOO
H3C
HO OH
O
OHHO
HO
OO
OHHO
HO
OHO HO NH
OOMe
OHOHHO
H3C
HO
HO
HO NH
OH
OHOHHO
H3C
HO
HO
Acarbose Methyl acarviosin 143
Pseudo-acarviosin 144
O
O
O OMeO OMe
O
OH
OHO OH
HO
HO OH
7 steps, 23.1%overall yield O
O
O OMeO OMe
NH2
OH1) NH2OH • HCl2) Raney Ni, H2
EtOH, Et3N
85%
HO
HO
HO OH
NH2
OHTFA, H2OCH2Cl2
88%HO
HO
HO OH
NH
OH
Valiolamine 19VogliboseAO-128 18
D-Glucose 131 142
OH
OH
HO NH
OH
OHOHHO HO
HO
CH3CN, Et3N, rt+
Pd(dba)2, TMPP
145
H2N
O O
OTBS
OMeMeO
146
O
O
O OMeO OMe
Cl
O
HO
HO OH
OH
HOO
OH
OHHO
HO
O
O OOP
dba =
TMPP =
D-Glucose L-Arabinose
144
Figure 5. Acarbose and related compounds
Scheme 27. Synthesis of valiolamine 19
Scheme 28. Retrosyntheticanalysisofpseudo-acarviosin144
No.178
16
No.178
Thepalladium-catalysedcouplingplan is the resultofamassiveexperimentation.Weattemptedagreatmanycouplingreaction conditions between different partners, amine with mesylate, ketone, allylic epoxide, allyic cyclic sulphite, or allylic acetate.22 As most of the electrophiles are unstable under the conditions and elimination is the major side-reaction, noneofthecouplingreactionsgavethedesiredproductexceptforusingallylic chlorideas thecouplingpartner shown in Scheme29.23
Sincethecouplingconditionswereestablished,westartedtoconstructthetwocouplingpartners145 and 146. D-Glucosewas converted into aldol 130 as said earlier.19 Eliminationofthe alcohol in 130 followedbyreductionof theketonegroupin 147 produced allylic alcohol 148 which was separated from its epimer via an acetylation and deacetylation protocol. The isolated 148 was then transformed into the allylic chloride 145 bystandardreactions(Scheme30).
O
O
O OMeO OMe
O
OH
POCl3pyridine
99%
O
O
O OMeO OMe
OOHO OH
HO
HO OH
7 steps, 25.3%overall yield
L-proline, DMSO
NaBH4, CeCl3 • 7H2O O
O
O OMeO OMe
OH
MeOH, –20 °C
O
O
O OMeO OMe
OAcAc2O, DMAPEt3N, CH2Cl2
98%
O
O
O OMeO OMe
K2CO3, MeOH
99%
O
O
O OMeO OMe
O
O
O OMeO OMe
Cl1) MsCl, Et3N CH2Cl2
2) 3Å MS, nBu4NCl 84%
OH
O
O
O OMeO OMe
OH+
147130
148
D-Glucose
149150145
OAc
O
O O
MeO OMe
HO
NaHCO3, CH3CNrt, 100%
BnNHOH • HCl
OH
NO
Bn
OOMeO
OMeO
N
O
O
MeO
OMe
OH
Bn
ON
O
O
MeO
OMe
OH
BnN O
O
OOHMeO
OMe
BnN O
O
O OHMeO
OMe
Bn
153 (19%) 154 (43%) 155 (29%) 156 (7%)
+ + +2-propanol
40 °C, 9d
O
OHHO OH
OH
L-Arabinose
10 steps
ON
O
O
MeO
OMe
OH
Bn
157
ON
OO
MeO
OMe
OTBS
Bn
158
BnHN
O
O
MeO
OMe
OTBS
159
OMs
BnHN
O
O
MeO
OMe
OTBS
160
H2N
OO
MeO
OMe
OTBS
146
TBSCl, imidazole
DMF, 100%
1) Raney Ni, H2, EtOH
2) MsCl, Et3N, CH2Cl2
LiEt3BH, THF
90%
10% Pd/C, H2
EtOH, 100%
151152
86%
OBn
OBn
O
Cl
OBn
OBn
OBnO
OBn
+N
O
NMe2
R1
NR2
H
R1
R2
OMe2N
Pd(dba)2, TMPPEt3N, CH3CN
13-98% yield
Scheme 30. Preparationofallylicchloride145 from D-glucose
Scheme 31. Preparationofamine146 from L-arabinose
Scheme 29. Successfulcouplingreactionswhenallylicchloridewasused
No.178
17
On theotherhand, theaminecouplingpartner146 was assembled from L-arabinose via anINACreactionofaprotectedhept-6-enose 151as thekeystep(Scheme31).21 The major exo-cycloadduct 154 with a trans-ringfusionwasformedwiththecorrect stereochemistry. It isnoteworthy that the trans-fused exo-cycloadduct could only be harvested with the nitrone containinga trans-diacetalblockinggroup. Thecycloadduct154 was transformed readily into the cyclohexyl amine 146 usingstandardreactionswithagoodoverallyield.
Withthecouplingpartnersinourhand,palladiumcatalysedallylic substitution of chloride 145 with amine 146 proceeded with retentionofconfiguration togive theprotectedallylic
amine 161 (Scheme32). Hydrolysisgavethetargetmoleculepseudo-acarviosin 144whichwas shown to be a strongersucroseandglucoamylaseinhibitorthanacarbose.21
3c. Synthesis of Validoxylamine G
Capitalisingonthepalladium-catalysedallylicsubstitutionreaction, the silyl ether 162 of the afore-prepared amine 142 and allylic chloride 145 (botharedirectaldolproducts fromD-glucose)werecoupled together to formpseudo-glycosylamine 163 which on complete acidic deprotection afforded validoxylamineG164inagoodyield(Scheme33).19
O
O
O OMeO OMe
Cl
145
H2N
O OMeO OMe
OTBS
146
O
O
O OMeO OMe
HN
O OMeO OMe
OTBS
161
+
Pd(dba)2, TMPPEt3N, CH3CN
84%
HO
HO
HO OH
NH
HO OH
OHTFA, H2O, CH2Cl2
90%144
O
O
O OMeO OMe
NH2
OH TMSOTfEt3N, CH2Cl2 O
O
O OMeO OMe
NH2
OTMS
85%
TFAH2OCH2Cl2
Pd(dba)2TMPPEt3NCH3CN99%
O
O
O OMeO OMe
Cl
88%
+
O
O
O OMeO OMe
HN
OTMS
O
O
OOOMeMeO
HO
HO
HO OH
NH
OH
OH
OH
OHHO
Validoxylamine G 164163
142145162
O
O
O OMeO OMe
OHOHO OH
HO
HO OH
O
O
O OMeO OMe
O
O
O
O OMeO OMe
OTBS HO
HO
O OMeO OMe
OTBS
TBSCl imidazole CH2Cl2 80% AcOH
88%95%
K-selectrideTHF
99%
HO
R
O OMeO OMe
OTBS O
R
O OMeO OMe
OTBSO
R
HO OH
OH
PDC, 3Å MSCH2Cl2
TFA, H2OCH2Cl2
1) MsCl 2) LiEt3BH, 84%
or AcCl, 94%or TBSCl, 97%
8 steps, 25%overall yield
91-100% 87-90%
D-Glucose
(+)-Gabosine A R = H(+)-Gabosine D R = OAc(+)-Gabosine E R = OH
147 165
Scheme 32. Synthesis of pseudo-acarviosin 144
Scheme 33. SynthesisofvalidoxylamineG164
Scheme 34. SynthesesofgabosineA,D,andE
No.178
18
No.178
3d. Synthesis of Gabosines
A number of gabosineswere easily assembled fromD-glucosevia thedirectaldolstrategy.Onlyafewofthemareillustrated here.24,25 Thus the aforesaid enone 147wasregio-and stereo-selectively reduced to the a-allylic alcohol 165 in an excellentyield(Scheme34).Functionalgroupmanipulationof165withstandardreactionsthenfurnishedgabosineA,D,andEwithout incident.25
4. Carbocyclization of Carbohydrates via an Intramolecular Horner–Wadsworth–Emmons (HWE) Olefination
IntramolecularHWE olefinationwas introduced atthebeginningof thisarticle, interestingly, it isperhapsstillthebest strategy for a short andefficient carbocyclizationof carbohydrate. Towards this end,wegloballyprotectedD-gluconolactonewith2-methoxypropeneasmixedacetals166 (Scheme 35).26 Addition of methyl phosphonate carbanion followed by oxidation of the alcohol in 167 caused intramolecularHWEalkenation toproceedconcomitantly togivetheprotectedcyclohexanone169 in just 3 steps from the freesugar! Acidic removalof theacetalsaffordedgabosineI170 and regioselectiveacetylationat theprimaryalcoholprovidedgabosineG171. The relatively labile mixed acetal blockinggroupswereproblematic,butwehavecircumventedthisobstaclewithethoxymethyl(EOM)protectinggroup.27
SinceEOMprotected cyclohexanone172 could also besynthesized readily fromD-gluconolactone (Scheme36),application of this route to the syntheses of streptol and other gabosineswere accomplished.27,28 Exploiting this facilecarbocyclizationstrategy,weembarkedontheconstructionofsodium-dependentglucosecotransporter2(SGLT2)inhibitors.
SergliflozinisapotentSGLT2inhibitor,butwasabandonedforfurther investigationbecausephenylglycosidesareproneto hydrolysis and therefore not suitable for development into usefulmedicine.Replacingthesugarmoietyinsergliflozinwithapseudo-sugarunitwouldprovideastable“glycoside”173 as the“glycosidicbond”isnowanetherlinkage(Figure6).29
Thesyntheticavenuetowardspseudoglucopyranoside173 isshowninScheme37. Regio-andstereo-selectivereductionof 172gavea-alcohol 174 which was activated and displaced with chloride to b-chloride 175. Palladiumcatalysedallylicsubstitution of the allylic chloride 175 with phenolic alcohol 176 proceededwithretentionofconfigurationtoformallylicether177inanexcellentyield.CatalytichydrogenationfollowedbyacidremovaloftheEOMgroupsaffordedthetargetmolecule173which isapotentandselectiveSGLT2inhibitor. Otheranalogshavealsobeenmadeonextendingthiscarbocyclizationstrategy.30,31
OHO
HO OH
O
HO OO O
O
O O
MeO OMe72%
Me P
OOEtOEt
OHO
O
O O
MeO OMe
O
P
O
OEtOEt THF, –78 °C
O O
O
O O
MeO OMe
1) LDA,
TPAP, NMO3Å MS, CH3CN
2-methoxypropene
K2CO3, 43%
(±)-CSA, DMF
OO
O
O O
MeO OMe
O
P
O
OEtOEt
HO O
HO
HO OH95%
HO O
AcO
HO OH
TFA, H2O Collidine–40 °C to rt
65%
AcCl
(–)-Gabosine I 170 Gabosine G 171
CH2Cl2
D-Gluconolactone 166 167
169168
OHO
HO OH
O
HO
EOMO O
EOMO
EOMO OEOMD-Gluconolactone
172
in 3 steps as in Scheme 35
Scheme 35. SynthesesofgabosineIandG
Scheme 36. SynthesisofstableEOMblockedcyclohexanone172
No.178
19
Conclusion
InthisArticle,transformationofcarbohydratesintohighlyoxygenatedcycloalkanesandcycloalkeneshasbeendescribedusingfoursyntheticstrategies,namelyintramolecularnitrone-alkene and nitrile oxide-alkene cycloadditions, direct aldol addition,andHorner–Wadsworth–Emmons(HWE)olefination.Thelatterstrategyprobablyoffersthemostfacileandefficientavenue to the pseudo-D-glucopyranosemotif todate. Thecarbocyclizedintermediatescouldthenelaboratedintovarioustargetmolecules containing hydroxyl/amine functionalgroupsofdefinedstereochemistry. Consideringthelowcost,availabilityinlargequantities,andrichstereochemistryofsugarmolecules,carbohydratesareperhapstheidealstartingmaterialsfor theconstructionofheavilyoxygenatednaturalproductsormoleculeswithpharmaceutical implication. Researchtowardsthe syntheses of carbocyclic nucleosides should have received more attention.
Acknowlegments
The author wishes to thank the University of Manchester, theChineseUniversityofHongKongand theHongKongResearchGrantCouncil forsupporting theseworks. Sinceregratitudegoes tohis researchcollaboratorsandco-workersfor theireffortsandstimulating ideas,especially toProfessorTohruYamadaofKeioUniversityforhisunflaggingsupport,encouragement,andfriendship.
HO
HO
OHHO
O OMe
1) Pd(OH)2/C, EtOHH2, rt
2) HCl, H2O, EtOH
173, 66%
51
EOMO
EOMO
EOMO OEOM
Cl
175
RO
RO
ORRO
O OMeHO OMe
176
+Pd(dba)2, dppe
EOMO
EOMO
EOMO OEOM
Cl
175
EOMO
EOMO
EOMO OEOM
O
172
EOMO
EOMO
EOMO OEOM
OH
174
LiEt3BH
THF, 76%
MsCl, Et3N
nBu4NCl, 81%
177K2CO3, CH3CN
94%
HO
HO OHOH
O
OMe
OHO
HO OHOH
O
Sergliflozin
OMe
Pseudo-aryl Glucoside 173
Scheme 37. Synthesisofpseudo-arylglucopyranoside173
Figure 6. Structuresofsergliflozinandpseudo-arylglucoside173
No.178
20
No.178
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Introduction of the author:
Tony K. M. ShingProfessor, D.Sc.Department of Chemistry, Faculty of Science and Technology, Keio University
Professor Tony K. M. Shing obtained his first degree from the University of Hong Kong, his M.Sc. (analytical chemistry), Ph.D. (carbohydrate chemistry) and D.Sc. (organic synthesis) degrees from the University of London. After postdoctoral work at McGill University and Oxford University, Prof. Shing began his independent career at the University of Manchester England, as a New Blood Lecturer in 1984. He was visiting Associate Professor at the University of California, Irvine, before returning to Hong Kong
in 1990. He joined the Department of Chemistry at the Chinese University of Hong Kong (CUHK) as a Lecturer, was promoted to Senior Lecturer in 1993, and to full Professor in 1996. In 2016 August, he retired from CUHK and joined Sophia University as an Invited Visiting Professor. Professor Shing moved to Keio University in October last year and is now a full Professor at the Department of Chemistry. He is also the Chairman of the Hong Kong Section of the Royal Society of Chemistry. His research interest is on the syntheses of organic molecules with chemotherapeutic potential, namely anti-cancer, anti-viral, or anti-diabetic activity.