1 Synthesis of Natural Products Containing Medium-size Carbocycles by Ring-closing Alkene ...

44 Pages·2010·0.69 MB·English

1
1
SynthesisofNaturalProductsContainingMedium-size
Carbocyclesby Ring-closingAlkeneMetathesis
NicolasBlanchard and JacquesEustache
1.1
Introduction
Thischapterdealswiththesynthesisofnaturallyoccurringmolecules(orrelated
models)andfocusesontheconstructionofmedium-sizecarbocyclesbyring-closing
metathesis(RCM).Wehavearbitrarilychosentoorganizethischapterbyincreasing
ringsize.Strategicaspectsandpotentialproblemsarediscussed.
1.2
FormationofFive-memberedCarbocyclesbyRCM
Strategicpositioningofthedoublebondsofa1,6-dienepriortoRCMcanbeeffi-
cientlyaccomplishedvia[3,3]-sigmatropicrearrangements.Onlyselectedexamples
arediscussedbelow,basedonoriginalityandefficiencycriteria.Catalyticasymmet-
ricClaisenrearrangementwasreportedbyHiersemannetal.intheenantioselective
synthesis of the C10–C18 segment of ecklonialactone B (1), a C18-oxylipin iso-
lated from the brown algae Ecklonia stolonifera and Egregia menziessi [1]. The
[3,3]-sigmatropicrearrangementof2usingcatalyst3ledtotheacyclicα-ketoester
4 that can be reduced and cyclized to the corresponding disubstituted cyclopen-
tene5 using[Ru]-II.Furtherfunctionalgrouptransformationsled tothedesired
C10–C18fragment6ofthenaturalproduct(Scheme1.1).
A[3,3]-sigmatropicrearrangement/RCMsequence[2]wasalsousedasakeystep
inthetotalsynthesisofabioactivespirobenzofuran7isolatedfromthemycelium
culturesofAcremoniumsp.HKI0230[3].Thetwoconsecutivequaternarycenters
embedded in the 1,6-diene 9 are worthy of note in the context of cyclopentene
formation by RCM, and the five-membered ring compound 10 was obtained in
high yield (97%) using catalyst [Ru]-I. The same type of strategy was applied for
theefficientconstructionofthetwovicinalquaternarycarbonatomspresentinthe
herbertanessesquiterpenes(Scheme1.2)[4].
Besides the Ireland–Claisen [3,3]-sigmatropic rearrangement/RCM sequence,
someexamplesofJohnson–Claisen/RCMwerereportedbyGhoshandMaity[5].
MetathesisinNaturalProductSynthesis:Strategies,SubstratesandCatalysts.EditedbyJanineCossy,
StelliosArseniyadis,andChristopheMeyer
Copyright2010WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:978-3-527-32440-8
2 1 SynthesisofNaturalProductsContainingMedium-sizeCarbocycles
2+
O O
2 SbF −
N N 6
CO Me Cu
2 t-Bu H OOH t-Bu H CO2Me
O 2 2 1. K-selectride
3 (7.5 mol%) O (dr > 95 : 5)
BnO OBn
CF3CH2OH, CH2Cl2 H 2. [Ru]-II (1 mol%)
rt, 3d
Cl(CH ) Cl
2 92% 4 75% (22 s2teps)
(dr > 95 : 5, ee = 92%)
Et Et
CO2Me H H O
Steps OH 16 1 O
OH 13
OBn ( )
OBn O O 7
H H
10
5 6 (−)-Ecklonialactone B (1)
Scheme 1.1
O
1. LDA [Ru]-I
TMSCl·Et3N (5 mol%) Steps HO
OH
Ar O 2. RHeCfllux then Ar CO2Me CH927C%l2, rt Ar CO2Me O
O 3. CH2N2 Spirobenzofuran from
8 9 10 Acremonium sp. HKI
Ar = 2,5-Dimethoxy-4-methylphenyl 0230 (7)
Scheme 1.2
OH
O O pCroHp3ioCn(Oic Eatc)3id O O Steps O O (4[ Rmuo]l-%I) O O Steps
Xylene6s6,% 140 °C PMB CH821C%l2, rt PMB
OH
COEt HO
2 HO
HO
12 13 14 15 Sequosempervirin
A (11)
Scheme 1.3
In the firsttotalsynthesis ofsequosempervirinA(11), anorlignan isolatedfrom
Sequoiasempervirens,theγ,δ-unsaturatedcarbonylderivative13waspreparedfrom
12byJohnson–Claisenrearrangement.Furtherstepsledto14,theprecursorofthe
keyRCMreactioncatalyzedby[Ru]-I,whichestablishedthedesiredspirostructure
ofcompound15(Scheme1.3).
An analogous Johnson–Claisen rearrangement/RCM sequence was used by
Ghosh etal. in the synthesis of the carbocyclic core of the nucleoside (−)-BCA
(16),apotentialinhibitorofHIVreversetranscriptase(Scheme1.4)[6].Thechiral
cyclopentene 20 was obtained in excellent yield through a [Ru]-I-mediated RCM
of1,6-diene19.Furtherepoxidationand functionalgrouptransformationsledto
(−)-BCAcorestructure23.
1.2 FormationofFive-memberedCarbocyclesbyRCM 3
NH
2
HO N N
N N
HO
Bis(hydroxymethyl)cyclopentenyl adenine, (−)-BCA (16)
CHC(OEt)
prop3ionic ac3id O Steps O O H [Ru]-I
O
O 140 °C, 6 h O C6H6, 60 °C, 20 h
68% 96%
EtOC
OH COEt 2
17 18 2 19
(dr = 1 : 1) (dr = 3 : 1)
BnO BnO HO
O O H Steps H m-CPBA H O Steps NH
2
BnO 85% BnO HO
EtOC
2
20 21 22 23
Scheme 1.4
1. LDA Steps OH
O
MeO C
2
2. HCl
O
3. CH N
2 2
25 26 27
OH
[Ru]-II HO Moist
(15 mol%) SiO Steps
2
p-Tol
CH Cl
2 2
28 29 Laurokamurene B (24)
Scheme 1.5
Another [3,3]-sigmatropic rearrangement/RCM sequence was developed by
Srikrishna and coworkers in the first total synthesis of the aromatic sesquiter-
pene(±)-laurokamureneB(24)(Scheme1.5)[7].RCMof27ledtocyclopentenol
28bearingalabilehydroxylmoiety,bothbenzylicandallylic.Thelattercompound
wasfoundtobeunstableandwhentreatedwithsilicageldeliveredtherearranged
alcohol29inaone-potoperation.
Derivativesofnitiol(30),anovelcomplexsesterterpenoidthatactsasamodulator
ofIL-2geneexpression,werepreparedusingRCMofvinylketone33asakeystep
(Scheme1.6)[8].Worthyofnoteistheuseofcatalyst[Ru]-XIII[9]as[Ru]-IIwas
found to increase intermolecular cross-metathesis at the expense of the desired
4 1 SynthesisofNaturalProductsContainingMedium-sizeCarbocycles
OH
H H
HO HO
Nitiol (30) 1,22-Dihydroxynitianes
O O O
[Ru]-XIII
OPMB OPMB OPMB
O ( )4 LDA HO ( )2 Steps ( )2 (5 mol%)
TMSCl, Et3N CH2Cl2, 40 °C
81%
31 32 33
OTBS
SnBu3 OPMB
O 1. LiHB(s-Bu)3 OSO2CF3 36 CO2Me OTBS( )3
( )2OPMB 2. PhNTf2 ( )2OPMB CaCt.u PCdl,( PLPiChl3)4
COMe
2
34 35 37
Scheme 1.6
RCM.Conjugatereductionofenone34usingl-selectridefollowedbytrappingof
the resulting enolate with PhNTf delivered enol triflate 35. The latter was then
2
submittedtoaStillecross-couplingreactionwithvinylstannane36leadingtothe
advancedintermediate37inthesynthesisof1,22-dihydroxynitianes.
In the total synthesis of (−)-allosamizoline (38), the carbocyclic fragment of
the chitinase inhibitor allosamidin, Donohoe and Rosa reported the efficient
elaborationofthe cyclopentenylmoietyviathe RCM of a1,6-diene (Scheme 1.7)
[10].Wittigolefinationofaldehyde39,readilyobtainedfromd-glucosamine,proved
troublesomewhenbasicphosphorusylide40was usedand the1,6-diene42was
isolated in 18% yield. Since the terminal substituents of the alkenes are not
transferred into the cyclized products during RCM reactions, the reactivity of
acrylate43wasevaluatedasthelatterwasobtainedinhighyield(91%)usingthe
lessbasicylide41.RCMproceedsequallywell,deliveringcyclopentene44in88%
yield.
Formation of cyclopentenes through the RCM of 1,6-dienes can prove itself
difficult in very crowded environment. During synthetic efforts toward the tetra-
cyclic skeleton of the sesquiterpenoid tashironin (47), Mehta and Maity reported
the efficient RCM of 50 using [Ru]-I that led to 51 in 86% yield [11]. However,
theRCMof52havingamethylsubstituentinallylicpositionledto53inconsid-
erably lower yield (25%) even in the presence of the more active [Ru]-II catalyst
(Scheme1.8).
ArapidelaborationoftheABCcorestructureofthetetranortriterpenedumsin
(54)wasreportedbySrikrishnaetal.startingfromthereadilyavailable(R)-carvone
[12]. Two independent efficient RCM reactions, catalyzed by [Ru]-I, were used as
1.2 FormationofFive-memberedCarbocyclesbyRCM 5
PhP=CHR
40:3 R = H [Ru]-II
MMOOMMOO NHCO2OMe 4T1o:l uRe n=e C, O902 M°Ce MMOOMMOO NHCO2MeR (1T09o 0lmu °eoCnl%e) MOMO OMOMNHCO2Me
39 44
42: R = H (18%) 80% (from 48)
43: R = COMe (91%) 88% (from 49)
2
O O NMe2 O NMe2
Steps MOMO N NMe2 1. NIS N Steps HO N
H
OMOM 2. AllylSnBu3 MOMO HO
AIBN OMOM OH
45 46 (−)-Allosamizoline (38)
Scheme 1.7
OH
OH O O [Ru]-I O
MeO PhI(OCOCF3)2 MeO O [4+2] MeO O (10 mol%) MeO O
THF, rt Toluene CH
6 6
40% reflux reflux
76% 86%
48 49 50 51
O O OH O
MeO O [Ru]-II (20 mol%) MeO O BzO O RO O
CH, reflux 25% OH O
6 6 O
52 53 Tashironin (47) Tetracylic core
structure
Scheme 1.8
O O [Ru]-I O
Steps (5 mol%) 1. AllylZnBr Li, liq NH
3
CHCl 2. PCC Allyl bromide
2 2 O
99% THF/t-BuOH
(R)-Carvone 55 56 57
O
AcO RCM RCM
O AcO
[Ru]-I C
(5 mol%) HO A D A C
O C1H002C%l2 O OA′H BH OO H BH O
58 59 O iBu
Dumsin (54) Dumsin ABC tricycle
Scheme 1.9
keystepstocreatethespirocyclopenteneincompound56andthetrans-fusedBC
ringsincompound59(Scheme1.9).
In challenging cases, simple transformations of the allylic substituents may
promote a productive RCM of 1,6-dienes to the corresponding cyclopentenes as
shown by Eustache etal. in the stereoselective synthesis of spiroepoxide 61, a
6 1 SynthesisofNaturalProductsContainingMedium-sizeCarbocycles
O
O
O
OMe
O CO2H OMe
O
Fumagillin (60) Spiroepoxide analog (61)
PMPO PMPO
O [Ru]-II O HO [Ru]-II HO
i-Bu (15 mol%) i-Bu i-Bu(15 mol%) i-Bu
OMe T7o0lu °eCne OMe OMOM C4H02 °CCl2 OMOM
30% 42%
62 63 66 67
Dess–Martin
NaBH4, CeCl3·7H2O periodinane BF·SMe
MeOH, 0 °C CH2Cl2, 20 °C CH32Cl2, −278 °C
55% (3 steps)
PMPO PMPO
OH [Ru]-II HO HO [Ru]-II HO
i-Bu (15 mol%) i-Bu i-Bu (5 mol%) i-Bu
CHCl
OMe 402 °C2 OMe OH C4H02 °CCl2 OH
64 65 68 80% 69
Scheme 1.10
potential methionine aminopeptidase-2 inhibitor related to the natural product
fumagillin (60) (Scheme 1.10) [13]. Actually, the RCM of vinyl ketone 62 was
◦
foundtobesluggishusingcatalyst[Ru]-II(toluene,70 C)yieldingonly30%ofthe
cyclopentenone63.Theenhancedreactivityofthecorrespondingallylicalcohol64
allowedasignificantyieldincrease(55%,overthreestepsfrom62).However,the
presenceofapotentialcoordinationsiteforthecatalystcouldalsobedetrimental
totheefficiencyoftheRCM.Thus,RCMoftheMethoxymethyl(MOM)ether66
gave cyclopentene 67 in moderate yield (42%), whereas the corresponding free
alcohol68cyclizedto69in80%yieldwithathreefolddecreaseincatalystloading
(Scheme1.10).
Cyclopentenesbearingatrisubstituteddoublebondcouldbeefficientlyprepared
via the RCM of the corresponding 1,6-diene. Catalyst [Ru]-II is well suited for
this transformation since [Ru]-I usually leads to inferior yields. The prochiral
trisubstitutedolefincouldthenbefurtherreducedoroxidized,thuscreatinganew
tertiaryorquaternarystereogeniccenter.
Trauner etal. used RCM as a key step to elaborate the cyclopentyl core of
(−)-guanacastepene E (70) and (−)-heptemerone B (71) (Scheme 1.11) [14]. The
cyclizationprecursorwaspreparedviaanasymmetricenereactionofglyoxylate72.
Furthertransformationsledto1,6-diene74thatcouldbecyclizedtocyclopentenone
75 in 86%yield using [Ru]-II (5mol%).Conjugateaddition ofthe organocuprate
76thenestablishedtheC11quaternarystereocenter.Thecentralseven-membered
ringwasthenclosedwithanelectrochemicaloxidation.
Fomannosin(79)isasesquiterpenemetaboliteisolatedfromthewood-destroying
BasidiomycetesfungusFomesannonsus(Fr.)Karst.Itsinherentinstabilityandvery
congested structure have elicited a great deal of interest from the synthetic
1.2 FormationofFive-memberedCarbocyclesbyRCM 7
O Steps [Ru]-II (5 mol%)
R*O R*O
SnCl, −78 °C OH OBn Toluene, reflux OBn
4
O O O 86% O
72 73 74 75
(dr = 10 : 1)
R = (1S,2R)-2-Phenylcyclohexyl
Cu(CN)(2-Th)Li
2
PO
O 1. KHMDS
76: P = TBDPS 11 2. TBSOTf
PO PO
THBFF,3 ·−O4E0t 2°C O O OBn 3. oAxnidoadticion O HO OBn
77 78
Steps
RO
O H OAc
O
R = H: (−)-Guanacastepene E (70)
R = Ac: Heptemerone B (71)
Scheme 1.11
PO O OMe Cp2ZrBu2 Steps (5[ Rmuo]-l%II)
OP
OP CH OP
OPMB PMBO OH re6flu6x
PMBO OTBS 91% PMBO OTBS
80: P = TBDPS 81 82 83
(dr = 2.4 : 1)
O O O
Steps O SEt 1. IBX, DMSO O Steps O
THF 2. Pd/C, EtSiH
PMBO OH silica gel3 PMBO OH O O
OH OH
84 85 (+)-Fomannosin (79)
Scheme 1.12
community.Paquetteetal.reportedastraightforwardstrategyfortheelaboration
of both antipodes of fomannosin. Compound 80 (prepared from α-d-glucose)
underwentazirconium-promotedringcontractionprovidingthefour-membered
ring81.ThechallengingRCMof82catalyzedby[Ru]-IIwasusedasakeystep,and
ledtocyclopentenederivative83featuringatrisubstituteddoublebondadjacentto
8 1 SynthesisofNaturalProductsContainingMedium-sizeCarbocycles
OH OH OMe HO OMe
OHC Steps [Ru]-II Br2, OEt
Br OBn CH2Cl2 OBn 91%
reflux, 20 h
OMe OMe
88%
87 88 89
EtO O OMe OBn EtO O OMe OBn O
Br
Bu3SnH Steps HO2C
OH
AIBN
OMe 85% OMe O
90 91 (+)-Puraquinonic acid (86)
Scheme 1.13
HO HO
O OR OH
HO HO
HO OH HO OH
Galactofuranosides (92) Carbagalactofuranose (93)
BnO BnO
[Ru]-II (10 mol%) OH
BnO OH BnO
Toluene, 60 °C,
BnO OH BnO OH
24 h 24%
94 95
BnO BnO
[Ru]-II (8 mol%) OAc
BnO OAc BnO
Toluene, 60 °C,
BnO OAc BnO OAc
24 h 89%
96 97
Scheme 1.14
aquaternarystereocenter(Scheme1.12)[15].Thelactoneringwasthenelaborated
byanintramolecularKnoevenagelreaction.
RCM was used as a key step in the total synthesis of (+)-puraquinonic acid
(86), afungalmetabolitethat inducesdifferentiation inHL-60 cells [16]. Starting
from aromatic aldehyde 87, the RCM precursor 88 was prepared in a few steps.
Following RCM leading to 89 (88%), the newly formedtrisubstitutedalkene was
involved in a radical cyclization. Bromo acetal 90 was treated with Bu SnH and
3
AIBNthustriggeringastereoselective5-exotrigcyclizationreaction.Furthersteps
ledtothenaturalproduct86(Scheme1.13).
Carbahexofuranoses and carbapentofuranoses syntheses have been intensively
investigated and RCM reaction emerged as one of the most practical and effi-
cientmethodstothiseffect.Amongthenumeroussynthesesofsuchderivatives,
1.2 FormationofFive-memberedCarbocyclesbyRCM 9
the synthesis of 4α-carba-β-d-galactofuranose 93 is worthy of note [17]. A dra-
matic protecting group effect was observed during the RCM of 94 and 96.
Whereas free allylic alcohols are known to enhance reactivity, RCM of 94
leads to the five-membered ring 95 in poor yield (24%). Under the same con-
ditions, the diacetate 96 undergoes an efficient RCM providing 97 in 89% yield
(Scheme1.14).
TwosimultaneousRCMhavebeenusedineffortstowardthecorestructureof
theelisabethinditerpenoids[18].Trisallylcarveol(99),accessiblefrom(R)-carvone,
canbetransformedinasinglestepundermildconditionsalbeitwithamoderate
yieldintothetricycliccompound100possessingthecorestructureofthedesired
targetmolecule(Scheme1.15).
Tetrasubstituteddouble bonds embeddedin a five-memberedring can also be
efficientlypreparedviaRCM.Inthetotalsynthesisof(±)-spirotenuipesinesA(101)
H
[Ru]-I
Steps (5 mol%)
CHCl O H
O OH reflux2, 242 h OH O
40% Me
OH
(R)-Carvone 99 100 Elisabethin A (98)
Scheme 1.15
OAc
TBSO [Ru]-II
HO
(5 mol%) Steps Cu(II) cat
O
OH C6H6 OTBS
reflux N2 O
82%
103 104 105
AcO MeS(S)CO
BuSnH
3
Steps AIBN
H H H H
O O Toluene O O
O O O O
106 107 108
HO HO
I O O
1. KOH
MeOH O Steps O O
O OH O
2. HCl
3. I, KI
2
NaHCO3 HO HO
109 Spirotenuipesine B Spirotenuipesine A
(102) (101)
Scheme 1.16
10 1 SynthesisofNaturalProductsContainingMedium-sizeCarbocycles
and B (102), Danishefsky etal. simplified the preparation of a key intermediate,
compound 104, from nine steps [19] to three steps when an RCM strategy was
adopted (Scheme 1.16) [20]. The resulting tetrasubstituted double bond in 104
was then submitted to an intramolecular diazoester cyclopropanation reaction.
Radical opening of the resulting strained cyclopropyl group in 107 delivered
bicyclic lactone 108, which was converted to 109 by iodolactonization. The latter
compound could be further transformed to (±)-spirotenuipesines A (101) and
B(102).
Another example of elaboration of tetrasubstituted double bonds by RCM was
disclosed by Kotora etal. in a formal total synthesis of estrone (Scheme 1.17).
Starting from 110, two zirconium-mediated cyclizations enabled the preparation
◦
of compound 112 whose RCM catalyzed by [Ru]-II (20mol%) (toluene, 90 C)
providedestroneprecursor113in82%yield[21].
MeO
H F
1. Cp ZrBu 1. Cp ZrBu
2 2 2 2
2. CuCl 2. Methallyl chloride
MeO (10 mol%) MeO CuCl (10 mol%)
F
110 111
Cl
[Ru]-II
H H
(20 mol%) Steps
Estrone
Toluene, 90 °C
MeO MeO
82%
112 113
Scheme 1.17
1. LDA H
O O 2. PhSe O O
O N 3. Bu4NIO4 OPMB X * Steps
N
55%
Bn OH
115 OPMB 116
X *
N
O Ti[(ROui-]P-I,r)4 O Steps 82 O314O1′2′ 3′ 4′ 5′
CHCl, 55 °C 7 5
OMe 2 2 OMe 6 OMe
OPMB 53% OPMB OH
117 118 Fumagillol (114)
Scheme 1.18