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[4+3] [4+3] Cycloaddition Cycloaddition Towards Natural Product SynthesisTowards Natural Product Synthesis
SULAGNA PAULMarch 15th, 2005
Michigan State University
O
CH2OHH
OH
iPrOH
Me
Me Me
HO
HMe
OOMe
MeOMeO
MeONHAc
O
O HH
HO
O
O
O
H
OAcCO2Me
OAc
[4+3]
Direct Formation of Seven-Member Ring System
Dieckmann condensation:
Jacob, T. M.; Vatakencherry, P. A.; Dev, S. Tetrahedron 1964, 20, 2815.
CO2EtCO2Et
o
CO2EtNaH
Ether, 15h(85–90%)
Ruzicka cyclization:
Krapcho, A. P.; Mundy, B. P. J. Org. Chem. 1967, 32, 2041.
CO2HCO2HO
H
H
O
H
H
OFe
Ba(OH)2
(24%)
Thorpe–Ziegler reaction:
Direct Formation of Seven-Member Ring System
Allinger, N. L.; Zalkow, V. B. J. Am. Chem. Soc. 1961, 83, 1144.
Acid–mediated olefin cyclization:
Marshall, J. A.; Anderson, N. H.; Johnson, P. C. J. Org. Chem. 1970, 35, 186.
CHOOH
Silica gel
2–5% ether–C6H6
(80%)
CNCN
H
H
H
H
O
1. Ph(Me)N–Li+ PhBr, Ether
RT, 48h
(58%)
2. HCl 25 ºC, 0.5h
Direct Formation of Seven-Member Ring System
Ring expansion:
Heathcock, C. H.; Delmar, E. G.; Graham, S. L. J. Am. Chem. Soc. 1982, 104, 1907.
Radical–induced cyclisation:
Duffault, J. M.; Tellier, F. Synthetic Communication. 1998, 28, 2467.
I
O O
O7–endoBu3SnH,cat. AIBN
C6H6, RT–0 ºC4hO O O
O6–exo
O
O
O
O
OOH
OAc
TsO
AcO
HO
1. KOH, tBuOH RT, 6h
(61%)
2. Ac2O, Py RT, 2d
Direct Formation of Seven-Member Ring System
Olefin metathesis:
Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.; Smith, D. W.; Schulz, G. R.; Wagener,K. B. J. Am. Chem. Soc. 1992, 114, 10978.
O O
[CH3(CF3)2CO]2
NMo
1h, 95%
[5+2] Cycloaddition:
Taninu, K.; Kondo, F.; Shimizu, T.; Miyashita, M. Org. Lett. 2002, 4, 2217.
OTIPS
BzOCo(CO)3Co(CO)3
OTIPSTIPSO
H
O
Co(CO)3Co(CO)3
EtAlCl2
CH2Cl298%
Features
[4+3] Cycloaddition:
Involves an electron rich (4π electron, 4 Carbon) diene reacting with allylic cation(2π electron, 3 Carbon).
[4+3]
Fort, A. W. J. Am. Chem. Soc. 1962, 84, 4979.
First example of [4+3] Cycloaddition:
Ph Ph
Cl
OPh Ph
O–O
O
Ph
Ph
O2,6–lutidine
DMF, RT 96h, 18%
Class A: Concerted bond–formation
Mechanistic Categories
Z Y Z Y Z Y
transition state
Class B: Stepwise bond–formation
Z Y Z Y Z Y
intermediate
Hoffman, H. M. R. Angew. Chem. Int. Ed. Engl. 1984, 23, 1.
OH
OH
Entended (Chair like) Compact (Boat like) endoexo
Nucleophilicity of the diene electrophilicity of the allyl cation
Z Y—H+
The Nucleophilicity of the Diene
s–cis–1, 3–Butadiene:
Stepwise process is lower in energy Preference for [3+2] over [4+3] Two competitive [3+2] pathway Lowest energy pathway— [3+2]/ Claisen rearrangement
Cramer, C. J.; Barrows, S. E. J. Org. Chem. 1998, 63, 5523.
ΔG≠ [4+3] C—C 8.2 kcal/mol[3+2] C—O 1.2 kcal/mol[3+2] C—C 2.0 kcal/mol
OH
OH
[4+3]
OH
HO[3+2]
Claisenrearrangement
[4+3]
OH[3+2]
The Nucleophilicity of the Diene
1, 3–Cyclopentadiene:
Furan:
Stepwise. The intermediate is very stable for its substantial oxonium ion character— favors direct [4+3].
Pyrrol:
1–Azabutadienyl cation is so stable – no bond closure steps are energetically favorable. Generates electrophilic substitution product.
Cramer, C. J.; Barrows, S. E. J. Org. Chem. 1998, 63, 5523.
Completely Stepwise— more nucleophilic. Small preference for [3+2] over [4+3]— allyl cation is monosubstituted at either end.[3+2]
[4+3]
OH
O
OH
O
OH
OH
HNHN
OH
HN
OH
OH
OH
O
The Electrophilicity of the Allyl Cation
Lithium oxyallyl cation:
Order of free energy, TS 1>TS 2> TS 3 —favoring concerted pathway. Activation energy for Claisen rearrangement is higher than hydroxy analog. Order of free energy of the product, compact > extended.
Cramer, C. J.; Barrow, S. E. J. Phys. Org. Chem. 2000, 13, 176.
Sodium oxyallyl cation:
Concerted pathway is favorable over stepwise. Free energy for TS 1> TS 2> TS 3— the difference in energy is smaller than before. Free energy for extended is slightly less than compact product.
ONa
Oxyallyl:
O Uncharged species— TS1 for stepwise is too unfavorable. Free energy of activation for TS 3> TS 2. Free energy for products compact> extended cycloadduct.
OLi
OLi OLi
[4+3]
TS 2LiO Li
O
TS 3
[3+2]
OLi
extended
compact
OLiTS 1
IN
Claisen
rearrangement
Allyl Cation in [4+3] Cycloaddition
Oxyallyl
NR
OOSiMe3
RO
OR
TMS
2–Aminoallyl Allyl acetal
α, β– Unsaturated carbonyl
O
Configuration of the transient allyl cation:
RR
OM
R
OMR R
OMR
The ‘U’ form The ‘Sickle’ form The ‘W’ form
Allyl cation precursors:
Oxyallyl Cation Reductive condition:
Hoffmann, H. M. R. Angew. Chem. Int. Ed. Engl. 1984, 23, 1.
Br
O
Br
O O O
O O O
O
ConditionsCu, NaI 48% 5% —
Zn, Cu 69% 8% 7%
Fe2(CO)9 40% — 50%
Shimizu, N.; Tanaka, M.; Tsuno, Y. J. Am. Chem. Soc. 1982, 104, 1330.
Solvolysis Condition:
O O O
O O O
t–Bu t–But–But–Bu
Cl
OTMSAgClO4
O
SolventTHF–Et2O 16% 22% 10% 40% 12%MeNO2 63% 37% — — —
OH
OTMS
OH
OTMS
(Z:E= 67:33)
Oxyallyl Cation Lewis acid catalyzed cycloaddition:
Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50.
ON
O
[O]— 45ºC N
OO
RR
Ochiral allenamide
NO
O
OR
H
nitrogen-stabilized oxyallyl cation
NO
O
R
X
— 45 ºC[4 + 3]
92% de
X
O
H
X = O or CH2
NO
R
O
OZn
Cl
ClH
X
blocking endo-2
endo-1
NO
O
OLA
LL
H
X
R
R
chiral Lewis acid-achiral allenamide
catalytic asymmetric[4 + 3] cycloadditions
NO
O
X
O
HR
X
O
H
N
O O
S
endo
Chiral Lewis Acid Catalyzed Enantioselective[4+3] Cycloaddition
Cu(OTf)2 (equiv) Ligand Equiv Temp ºC %Yield % ee 0.85 A 1.1 —55 62 78[S]
0.25 B 0.32 —78 46 82[S] 0.10 C 0.12 —78 76 59[S]
N
O
N
O
Ph PhN
O
N
O
Ph Ph
Ph PhN
O
N
OHH
Ph Ph
Ph Ph
A B C
Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50.
ON
O
allenamide
Pre-mixed Cu(OTf)2 and ligand9.0 equiv of furan
3-5 equiv DMDO/syringe pump add.CH2Cl2 [0.05M], 8-10 h
NO
O
O
O
HR
O
O
H
N
O O
S
Chiral Lewis Acid Catalyzed Enantioselective[4+3] Cycloaddition
Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50.
OHH
endo–1N
OO
X
O
HR
endo-1
SIDE VIEW
NO
O
OCu
N
NO
O
OHHendo–2
X
O
H
N
O O
S
endo-2
favoured due to less steric
Chiral Lewis Acid Catalyzed Enantioselective[4+3] Cycloaddition
Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50.
Entry Dienes R additive product % Yield %ee
1 — — [S] 90 92
2 — AgSbF6 [S] 91 99
3 Me AgSbF6 [S] (20:1) 88 71
4 CO2Me AgSbF6 [S] (syn only) 61 67
5 — — [S] 81 36
6 Me AgSbF6 [S] (anti only) 91 99
O
O R
O MeMe
O
R
O
O
H
N
O O
SON
OO
O
H
N
O O
SR
R25mol% Cu(OTf)2, 32mol% C9.0 equiv diene, —78 ºC
2–5 equiv DMDO, syringe pump addAcetone/CH2Cl2 [0.05M], 8–10 h
4Aº Mol. Sieves and additivesyn anti
Chiral Lewis Acid Catalyzed Enantioselective[4+3] Cycloaddition
Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50.
TOP VIEWS
N
O
N
O
Ph Ph
Ph Ph
Cu
NO
OO
A
3R
O
R
O
O
H
N
O O
SR
syn
3L
O
R
O
O
H
N
O O
SR
anti
N
O
N
O
Ph Ph
Ph Ph
Cu
NO
OO
B OR
HH
R2R
2L
sliding over
Oxyallyl Cation
Intramolecular [4+3] cycloaddition:
The initial geometry of the allyl cation is irrelevant with respect to the yield and stereochemistry.
EtTolSO2
CH3
CH3
OO
CH3CH3
OEtTiCl4
CH2Cl2, —78 ºC74%
OCH3CH3
OEt
not formed
OEtp
OEtCH3
CH3O2SpTol
O
Et
(E)/(Z)
OCH3CH3
OEtTiCl4
CH2Cl2, —78 ºC58%
Harmata, M.; Gamlath, C. B. J. Org. Chem. 1988, 53, 6156.
Nature of Mechanism
Harmata, M.; Schreiner, P. R. Org. Lett. 2001, 3, 3663.
OCH3CH3
OEt
OCH3CH3
OEtEt
B'
OCH3
CH3
OEtEt
A'
TS1
A' –0.4
TS18.4
B' 4.0
OCH3CH3
OEt
OCH3CH3
OEtEt
B
OCH3
CH3
OEtEt
A
TS2
A –3.5
TS22.2
B –3.4
Allylic Acetals
Stark, C. B. W.; Eggert, U.; Hoffmann, H. M. R. Angew. Chem. Int. Ed. 1998, 37, 1266.
Diastereoselectivity attained by using chiral auxiliary in the form of mixed acetal.
Si OO
O
HHH
H
disfavored
O SiO
H
O
HHH
favored
OTESOCH3
O
Ph
O
O
O
OO O
Ph Ph
TMSOTf—95 ºC, 10min
Conditions Total Yield neat (—78 ºC, 30min) 2.9 : 1 54%MeNO2 4.1 : 1 36%DCM 7.5 : 1 67%DCM/pentane(—110 ºC) 8.2 : 1 37%
O
α,β—Unsaturated Carbonyl Compounds
Sasaki, T.; Ishibashi, Y.; Ohno, M. Tet. Lett. 1982, 23, 1693.
OSiMe3
OSiMe3
OSnCl4
COMeOSiMe3
COMeOH
OSiMe3OSnCl4
O
O
OSiMe3
OH
SnCl4
R = H
R = Me
O
R
H2O
H2O
(32 %)
(35 %)
Lewis Acid Catalyzed [4+3] Cycloaddition
Avenoza, A.; Busto, J. H.; Cativiela, C. Tet. Lett. 2002, 43, 4167.Arno, M.; Picher, M. T.; Domingo, L. R.; Andres, J. Chem. Eur. J. 2004, 10, 4742.
PhN O
Ph
O
PhN O
O
Ph
PhN O
O
Ph
ON
O
PhPh
–25 ºC
6h
ConditionAlCl3 (0.5 eq) 53 47 —AlCl3 (0.75 eq) 22 34 44AlCl2Et (0.75eq) 40 34 26AlCl2Et (1.5 eq, 0 ºC) — — 100
(3 eq)
PhN O
Ph
O
PhN O
O
Ph
PhN O
O
Ph
AlH3 AlH3 AlH3
Michael–typeaddition
PhN O
Ph
O
Friedel–Craft–typeaddition Ph N
O
OPh
AlH3
ON
O
PhPhAlH3
AlH3
Lewis Acid Catalyzed [4+3] Cycloaddition
PhN O
Ph
O
AlH3Ph
N
O
PhO AlH3
Ph N
O
OPh
AlH3
Ph N
O
OPh
AlH3
ON
O
PhPh
AlH3
TS 1
TS 2 TS 3
IN 1
IN 2
δ+
δ−
δ+
δ−
Arno, M.; Picher, M. T.; Domingo, L. R.; Andres, J. Chem. Eur. J. 2004, 10, 4742.
Mechanism for Friedel—Craft—type Addition:
2—Amino Allyl Cation
N
O
Bn NBnH
O
BF3 OEt2 (150 mol %)CH2Cl2, RT, 16h
67%
Prie, G.; Prevost, N.; Twin, H.; Fernandes, S. A.; Hayes, J. F.; Shipman, M. Angew. Chem. Int. Ed.2004, 43, 6517.
NR
X
NR
NRLA
NLA R N R
[4+3]
sBuLi then LA
2—Amino allyl cation
Prie, G.; Prevost, N.; Twin, H.; Fernandes, S. A.; Hayes, J. F.; Shipman, M. Angew. Chem. Int. Ed.2004, 43, 6517.
N
O
Bn NBnH
O
NBnH
O
1. BF3•OEt2 (150 mol %) CH2Cl2, 50 ºC, 16h
(Z) 56% (80:20)(E) 45% (32:68)
2. aq. H2SO4, MeOH 50 ºC,16h
NBn NBn
H
H
1. BF3•OEt2 (150 mol %) ClCH2CH2Cl,
reflux, 48h
53% (56:44)
2. aq. H2SO4, MeOH 16h
OH
NMe
H
F3B CH2Ph≠
OH
NH
Me
F3B CH2Ph≠
Straightforward and powerful approach for synthesizing seven member rings.
[4+3] Cycloaddition in Natural Product Synthesis
Sterpurene
H
OOMe
MeOMeO
MeONHAc
Me
MeMe
HO
HMe
O
O
H
OHOH
OH
iPrOHO
CH2OHH
Aphanamol I Lasidiol Dactylol
ColchicineSpatol Widdrol
O
O HH
HO
O
O
5–epi–10–epi–Vibsanin E
[4+3]
4–Substituted Butenolides
O OO OHnC8H17
Popillia japonica Eldana saccharina
Mori, K. Tetrahedron. 1989, 45, 3233.
O
O
O
OCO2R
OCO2R
OH
OH
OH
OH
OH
R
Synthetic building blocks
C1–C2 Cleavage: Preparation of 4–Substituted Butenolides
Montana, A. M.; Garcia, F.; Batalla, C. Tet. Lett. 2004, 45, 8549.
O OMeBr
O
BrO
O
OMe OO
O
O
O OMe
O
O O
1. Cu/NaI MeCN, RT 97% dr= 70:30
2. Chromatographic separation
HCl/MeOHRT, 10h
72%
HCl/MeOHRT, 25h
63%
H2/Pd—C100%
H2/Pd—C98%
O OR
OO
O
OO
O
OR
OCO2R
OCO2R
OH
OH
OH
OH
OH
R
Synthetic building blocks
Tricycloclavulone
Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563.
Isolated from soft coral Claularia viridis.
O
H
AcO CO2Me
OAc
Tricycloclavulone
O
H
AcO BrO
O
BrBr
Tricycloclavulone
Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563.
O
BrBr BrO O
BrTEA
TFE/ET2O, 1:1—78 ºC to RT
70% 6%
BrO O
O
H
HLiTHF
—78 to —30 ºC90%
CH2=CH2, CH2Cl2
5% G, RT,overnight,50%
O
H
AcORu
Ph
PCy3
PCy3
Cl
Cl= G
Aphanamol IThe first natural product synthesized using [4+3] cycloaddition.Isolated from the fruit peel of Indonesian timber tree Aphanamixis grandifolia.
Hansson, T.; Wickberg, B. J. Org. Chem. 1992, 57, 5370.
CHO
(PPh3)3RhClPhCN, 130 ºC, 1.5 h
90 %
(S)–A
O
BzO
(S)–Ahν
H H
OBz
O H OBz
H
O1:1
Me2S(O)=CH2
H OH
OBzO
H CH2OH
KOH/MeOHreflux, 2h
(+ )–Aphanamol I
Aphanamol IAdvantage of the direct formation of seven—membered rings by [4+3]cycloaddition.
Harmata, M.; Carter, K. W. Tet. Lett. 1997, 38, 7985.
P OEt
O
OEt
O
EtO
EtO 5
O
CH2OHH
8
OMOM
P
Li
O
Ph
Ph
2
CN
OMOM58%
3
OMOM
O
MeMgI
85%
1. LDA,
2. LAH 69%
4O
CH2OMOMH
7
Tf2O
CH2Cl2, 2,6–lutidine—78 ºC, 32%
H3O+
42%
OMOM
CH2OHEtO
6
(+ )–Aphanamol I
CN
CHO
1
Aphanamol ITransition metal catalyzed [5+2] cycloaddition
Wender, P. A.; Zhang, L. Org. Lett. 2000, 2, 2323.
OBn [5+2] cycloadditionH
OBn
0.5 mol% [Rh(CO)2Cl]2, 0.1M,Toluene, 110 ºC, 30 min, 93%
OxidativeAddition
RhLn
HOBn
Rotation and strain-drivenCyclopropane Cleavage
H
LnRh
OBn
ReductiveElimination
O
H
OH(+)–Aphanamol
OBn
•CHOOBn
CO2MeCO2Me
O
CO2Me
R–(+)–Limonene
Tropoloisoquiniline
OOR
OMeMeO
MeONHAc
OMeO
OMeMeO
MeONHAc N
ORO
MeO
MeO
MeO
N
OOMe
MeO
MeO
MeO
Colchicine (9): R = MeColchiceine (10): R = H
Isocolchicine Grandirubrine : R = HIsoimerubrine : R = Me Imerubrine
Lee, J. C.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 3243.
Colchicine
Lee, J. C.; Jin, S. J.; Cha, J. K. J. Org. Chem. 1998, 63, 2804.
The principle alkaloid constituent of Colchicum autamnale Biological activity: arrests cell division during mitosis, potential antitumor agent
OHMeO
MeOOMe
1
OMeMeO
MeONHAc
6
O
MeO
MeOOMe
OH
O
N
N
OLi
H3B
Swern [O];
61%2
MeO
MeOOMe
O
NHN Me
O
5
MeO
MeOOMe
R2
O
N1. Swern [O]
2. Itsuno red.
3: R2 = β–OH
4: R2 = α–N3
PPh3, DEAD(PhO)2P(O)N3
60%
82%
1. PPh3, H2O2. Ac2O, Et3N 95–100%
o–Cl2C6H4
reflux(60—70%)
Colchicine
Lee, J. C.; Jin, S. J.; Cha, J. K. J. Org. Chem. 1998, 63, 2804.
OMeMeO
MeONHAc
6
O
OTMS
OMe
OMe
OMeO
MeO
MeONHAc
OOMe
7
8
TMSOTfEtNO2–78 ~ 50 ºC (60%)
Undesired regioisomer
OMeMeO
MeONHAc
6
O OMeMeO
MeONHBOC
O
1. (BOC)2O2. LiOH
(98%)
OTMS
OMe
OMe
7TMSOTf (45%)
9
OMeO
MeO
MeONHBOC
O
OMe10
OOMe
MeOMeO
MeONHAc1. HCl
2. Ac2O (98%)
(—) Colchicine~ 90% ee
9
OOMe
MeOMeO
MeONHBOC
TMSOTfEt3N
CH2Cl2
0—10 ºC (62%)
11
Colchicine
Lee, J. C.; Jin, S. J.; Cha, J. K. J. Org. Chem. 1998, 63, 2804.
O
NAcMeO
MeOOMe
OMe
OTMS
H
OMeO
MeO
MeONHAcOMe
8
Undesired regioisomer
O
6
OMeO
MeO
MeONHBOC
O
O
NBOCMeO
MeOOMe
H
MeO
TMSO
9
OMe10
Tropoloisoquiniline
Lee, J. C.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 3243.
Grandirubrine : R = HIsoimerubrine : R = MeImerubrine
O
ORN
MeO
MeO
MeO
O
N
MeO
MeO
MeO
N O
NP
MeO
MeO
MeO
N O
or
NHTsOMe
OMe
Imerubrine was isolated from the plant Abuta imeneGrandirubrine was isolated from Abuta grandifolia
Tropoloisoquiniline
N
OOMe
MeO
MeO
MeO
Imerubrine
N
MeO
MeO
MeO
O
OCl Cl
ClN
MeO
MeO
MeO
OO
1. Et3N, CF3CH2OH2. Zn NH4Cl, MeOH
73%
N
MeO
MeO
MeO
O
OH
PhI(OAc)2KOH–MeOH 83%
OMeOMe
N
MeO
MeO
MeO
OO
OMe
1. NaH, MeI2. 50% AcOH
92%
TMSOTfEt3NCH2Cl2
76%
Lee, J. C.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 3243.
Tropoloisoquiniline
Lee, J. C.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 3243.
N
MeO
MeO
MeO
O
OH
OMeOMe
N
MeO
MeO
MeO
OO
OH
N
OHO
MeO
MeO
MeO
Grandirubrine
N
OMeO
MeO
MeO
MeO
Isoimerubrine
50% AcOH
96%
TMSOTfEt3NCH2Cl2
62%
TMSCHN2MeOH–THF
N
OOMe
MeO
MeO
MeO
Imerubrine (34%) (32%)
(+)—Dactylol
Feldman, K. S.; Wu, M. J.; Rotella, D. P. J. Am. Chem. Soc. 1989, 111, 6457.
(+)–Dactylol was isolated from sea hare Aplysia dactylomela.
Tropone– alkene photocyclization
O
hν
ORH
CH3H H
O
Me
Me
HO
HMeOR
R = HR = CH3CO
Me
MeMe
HO
HMe
(+)–Dactylol
(+)—Dactylol
Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 8746.
O O1. methallyl bromide
Mg-graphite (4.3 equiv) THF, 65 ºC, 30 min
RO
RO
2. CeCl3, –78 ºC, 2h 80% combined yield
1a R = H
2a R = H
1a: 2a = 1: 1.2 1b R = SiMe3
2b R = SiMe3
a (93%)
a (95%)
a. (Me3Si)2NH (1.25 equiv), acetyl chloride (1.25 equiv)
DMAP
HO
HO
H
b
b
b. 1.molybdenum carbene X (3 mol%), hexane, 55 ºC, 3
2. aq. TBAF, THF, 50 ºC, 3h
92%
85%
NMo
O
O
F3C CF3
F3CF3C
X
Ph
(+)—Dactylol
Harmata, M.; Rashatasakhon, P. Org. Lett. 2000, 2, 2913.
Me
MeMe
HO
HMe
(+)–Dactylol
Me
HMe
CO
OCl
Me
Me
TMS
OCO2Me
Me I
Me TMSA
(+)—Dactylol
Harmata, M.; Rashatasakhon, P. Org. Lett. 2000, 2, 2913.
OCO2Me
Me1. NaH; nBuLi2. A O
CO2Me
Me
Me
TMS
70%
KCN, DMSOreflux, 94% O
Me
Me
TMS
1. LDA, TfCl2. TEA; TFE/Et2O3. TsOH
74%
Me
HMe
CO
25:1
CH2I2, Et2Zn95%
Me
HMe
CO
MMPPDMF, 84%
Me
HMe
CO
O
4:1
O R
Me Me
(+)—Dactylol
Harmata, M.; Rashatasakhon, P. Org. Lett. 2000, 2, 2913.
Me
HMe
CO
Me Me
O 1. KOH2.CH2N2
Me
HMeMe Me
OHMeO O
1. POCl3, HMPAPyridine
2. KOH84%, 4 steps
Me
HMeMe Me
HO O
1. COCl2, DMF2. mCPBA, Pyridine/DMAP3. LAH, Et2O
50%
Me
HMeMe Me
HO
(+)–Dactylol
Me
HMe
CO
O H2/PtO298%
Vibsanin E
O
O
O
O
O
H
HH
Vibsanin E
UV [4+2]
hetero [4+2][4+3]
Vibsanin E was isolated from the plant Viburnum odoratissimum in 1980 Its absolute configuration was established by Fukuyama & et al in the same year Vibsanin family has been extensively used in medicines of menstrual cramps
O
O
O
O
Vibsanin C
OH
BF3•OEt2CH2Cl2, -78 ºC, 18 min
50%
O
O
O
O
O
H
HH
Vibsanin E
Fukuyama, Y.; Minami, H.; Kagawa, M.; Kodama, M.; Kawazu, K. J. Nat. Prod. 1999, 62, 337.
Davies, H. M.; Loe, O.; Stafford, D. G. Org. Lett. 2005, 7, 5561.
Attemped Total Synthesis of Vibasanin E
Synthesis of A
Synthesis of B
N2EWG
O
R
N2EWG
OH
R
N2EWG
R
NaBH4 POCl3
NEt3
Davies, H. M.; Loe, O.; Stafford, D. G. Org. Lett. 2005, 7, 5561.
OH O(COCl)2DMSO
CH2Cl2—50~—60 ºC
Ph3P CH2
THF
(90–94%) (77–80%)
CO2MeN2 CO2Me 1. Rh(II), hexane,
Overnight, rt2. toluene, reflux, 5h
Rh2(OOct)4 62% yield
Rh2(S-DOSP)4 69% yield (64% ee)
A B
Attemped Total Synthesis of Vibasanin E
Davies, H. M.; Loe, O.; Stafford, D. G. Org. Lett. 2005, 7, 5561.
tandem conjugateaddition/alkylation
O
H
H
HO
A
O
O
O
O
O
H
HH
Vibsanin E
tandem conjugateaddition/alkylation
O
H
H
HO
A
O
H
H
HO
only product that could be achievedvia Me2CuLi induced reaction.
resistant to conjugate addition(probably due to steric)
X
1. DIBAL-H2. (COCl)2 DMSO
90%
OBF3•OEt2
hetereo [4+2]
86%
O
H
H
NaCNBH3/
84%
AcOH
O
H
H
H
1. SeO22. PCC
O
H
H
HO
CO2Me
Atricyclic core of
Vibsanin E
Attemped Total Synthesis of Vibasanin E
O
H
H
HOO
H
H
HO
ACis
BTrans
hν
O
H
H
HO
A
UV/pyrex
91%
O
H
H
HO
B
O
H
H
HO
CB:C = 2:1
O
O
O
O
O
H
HH
Vibsanin E
OsO4/NMO
O
H
H
HO
D 46%
O
H
H
HO
E 25%
HO
HOHO
HO
Davies, H. M.; Loe, O.; Stafford, D. G. Org. Lett. 2005, 7, 5561.
O
O 2Py, Catalyst
N
N
Catalyst
O
O
O
O
O
H
HH O
O
H
HH
O
OO
G 19%(±)-5-epi-10-epi-Vibsanin E
H 10%
NaIO4O
O
O
O
H
HH
F 81%
Summary
[4+3] Cycloaddition reaction is one of the most synthetically useful method for synthesizing seven–member rings.
A 1,3 diene and an allyl cation cyclizes either in a concerted or stepwise fashion.
The reaction depends on the nucleophilicity of the diene and electrophilicity of the allyl cation.
Different allyl cation– 2–oxyallyl, 2–amino allyl, allyl acetal etc. are known.
The reaction shows high levels of stereoselectivity.
Successfully employed in synthesizing important building blocks and several natural products.
Acknowledgments
Dr. Smith
Dr. Maleczka
Dr. Walker
Dr. Smith’s Group members
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