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Studies Directed Toward Studies Directed Toward Synthesis of Hyperforin Synthesis of Hyperforin
and Related Phloroglucinsand Related Phloroglucins
Literature MeetingLiterature Meeting
Jad TannousJad TannousJanuary 16, 2006January 16, 2006
22
OutlineOutline
1.1. Introduction on the moleculesIntroduction on the molecules
2.2. HyperforinHyperforinI.I. Biosynthesis of HyperforinBiosynthesis of HyperforinII.II. Kraus Synthesis of the Bicylic CoreKraus Synthesis of the Bicylic CoreIII.III. Young Synthesis of the Bicylic CoreYoung Synthesis of the Bicylic CoreIV.IV. My Research at MerckMy Research at Merck
3.3. Garsubellin AGarsubellin AI.I. Takagi Development of the Bicyclo[3.3.1]nonenone Takagi Development of the Bicyclo[3.3.1]nonenone
CoreCoreII.II. Miesch New Cascade Reactions Starting from Miesch New Cascade Reactions Starting from
Acetylenic Acetylenic -ketoesters-ketoestersIII.III. Stoltz Progress Toward the Synthesis of Garsubellin Stoltz Progress Toward the Synthesis of Garsubellin
A A IV.IV. Nicolaou Synthesis of a Fully Fonctionalized Bicyclic Nicolaou Synthesis of a Fully Fonctionalized Bicyclic
CoreCoreV.V. Shibasaki Synthesis of (±)-Garsubellin AShibasaki Synthesis of (±)-Garsubellin A
33
The The MoleculesMolecules: Phloroglucins: Phloroglucins
OH
O
H3C
O
O
Hyperforin
H3C O
O
O O
HOH
H3C
Garsubellin A
Isolated fron Hypericum perforatum (St.John's Wort)
Photo and oxygen labile
Difficult to isolate in pure form
Known to aid wound healing
Has been studied for it's anti-depressant properties
Antibacterial activity (Gram-positive)
Isolated from Garcinia subelliptica
Highly oxygenated and densely fonctionalized
Might be efficient in curing Alzheimer disease by
increasing ChAT activity
44
The Molecules: More PhloroglucinsThe Molecules: More Phloroglucins
OH
OO O
H3C
H3C O
OO O
HOH
H3C
O
O
O
HO
HOO
O
O
O OH
OH
HO
HO
O
O
O
O
O
Fluronewguinone A Fluronewginone B Perforatumone
Harrison, L.J ., Tetrahedron Letters, 45, 2004, 9657-9659.
Sticher, O., Helvetica Chimica Acta, Vol.84, 2001, 3380-3392.
55
Biosynthesis of Hyperforin:Biosynthesis of Hyperforin:Biosynthesis of the hyperforin skeleton in Biosynthesis of the hyperforin skeleton in Hypericum calycinumHypericum calycinum cell cultures cell cultures
OH
O
H3C
O
O
HO OH
OHO
O
CoAS
Isobutyryl-CoA
66
Biosynthesis of Hyperforin:Biosynthesis of Hyperforin:First prenylation stepFirst prenylation step
HO OH
OHO
O
CoAS
Isobutyryl-CoA
3-Malonyl-CoA
O
O
SCoAO
O
P. Klingauf et al., Phytochemistry, 66, 2005, 139-145.
Phlorisobutyrophenone
HO OH
OHO
DMAPP
Z. Boubakir et al., Phytochemistry, 66, 2005, 51-57.
HO OH
OHO
77
Biosynthesis of Hyperforin:Biosynthesis of Hyperforin:Hypothetical mechanism of hyperforin biosynthesisHypothetical mechanism of hyperforin biosynthesis
HO OH
O
PPO
O
HO OH
OHO
OH
O
H3C
O
O
W. Einsenreich, J . Med. Chem., 45, 2002, 4786-4793.
88
Authors Who Have Worked on Authors Who Have Worked on Synthesis of PhloroglucinsSynthesis of Phloroglucins
Hyperforin:Kraus, Nicolaou, Young, Metha (enantioselective), …
Garsubellin A:Stoltz, Nicolaou, Shibasaki, Grossman, …
99
Studies towardStudies toward Hyperforin Hyperforin
What are the strategies?What are the strategies?
•Kraus: Allylation followed by Mn-mediated oxidative cyclization
•Nicolaou: annulation of the gem-dimethyl-containing ring onto an existing cyclohexanone
•Young: Intramolecular allene-nitrile oxide cycloaddition
1010
Kraus Synthesis of the Bicylic CoreKraus Synthesis of the Bicylic CoreO
R 1. NaH, CH2=CHCH2Br
2. Mn(OAc)3, Cu(OAc)2
O
H R
NBS (2,2 equiv)
O
H R
Br Br
NBS (1,1 equiv)
O
H R
Br Br
Br
O
H R
BrO
aq. HOAc
1. CH2=CHCH2OH, Na
O
H R2. 140-170 oC
O OH
56%
95% (3 steps)
R = CO2Et, COPh
45-52 overall yieldG. A. Kraus, Tetrahedron Letters, 44, 2003, 659-661.G. A. Kraus, Tetrahedron , 59, 2003, 8975-8978.
Me
O
CO2Me Me
O
CO2Me
SO2Ph
AcO
G. A. Kraus, Tetrahedron , 61, 2004, 2111-2116.
Na/ Hg
1111
Young Synthesis of the bicylic coreYoung Synthesis of the bicylic coreO
OHO
O O
OHN
O O
COR
NO2
D. G. Young, J . Org. Chem., 2002, 67, 3134-3137.
O
Ph
1. CeCl3, THF
Me MgBr
2. i) O3, CH2Cl2 ii) DMS
76%
OOH
LiAlH4, 86%
OHOH
Im2CO C6H699%
OO
O
OH
LiCuMe2, Et2O
C
96%O
COCl2, DMSO, Et3N
C
86%
1212
Young Synthesis of the bicylic coreYoung Synthesis of the bicylic coreO
OHO
O O
OHN
O O
COR
NO2
D. G. Young, J . Org. Chem., 2002, 67, 3134-3137.
OTMS
C
44%1:1 mixture
TiCl4OMe
MeO NO2
O
COMe
NO2
40%
PhNCO, NEt3
O
OMeN
O
O
OMeN
O
MeOH, 100%
Raney Ni, H2
O
OMeH2N
O
1313
My Research at MerckMy Research at Merck
OH3C
CH2OTES
CO2MeO
O
H3C
O
OTESOH
OH3C
CO2Me
OAc
O
H3C
O
HO
O
O
O O
O
O
Br
O
O
O
O
O
O
OH
O
H3C
O
O
O
O
O
Hyperforin
dianionchemistry
Dieckmanncyclization
Michael addition
alkylation
Birch reduction Stille reaction2 bromination1
1. J. Chem. Research(M); 1991; 367-3782. Synthesis; 1996; 475-482
1414
My Research at MerckMy Research at Merck
OH3C
CO2Me
O O
O
O
O
O
O
O
Alkylative carbonyl transpositionsequence
MichaelIntroduce a carboxylate
O
HO
Alkylation
1515
Synthesis and Studies towardSynthesis and Studies toward Garsubellin AGarsubellin A
What are the strategies?What are the strategies?
•Shibasaki: C-C bond forming addition-elimination and aldol reactions
•Nicolaou: « Biomimetic » selenocyclization of a cyclic B-keto ester onto a pendant prenyl group
•Stoltz: Tandem Claisen-Dieckmann reaction of malonyl dichloride
1616
Takagi Development of the Takagi Development of the Bicyclo[3.3.1]nonenone CoreBicyclo[3.3.1]nonenone Core
O
R3
R1
R2 LDA, THF, -78 oC
RO2C
OAc
O
R1
R2
R3CO2R K2CO3, TBAB
solvent
O
R3
R2 R1
RO2C
O
R3
R2 R1
RO2C
R3
R1
RO2C
O
R2
R. Takagi, Tetrahedron Letters, 45, 2004, 7401-7405.
H3C O
O
O O
HOH
H3C
Garsubellin A
O
R3
R2 R1
RO2C
R1 = H, EtOR2 = H, MeR3 = H, Me, CO2Et
1717
Takagi Development of the Takagi Development of the Bicyclo[3.3.1]nonenone CoreBicyclo[3.3.1]nonenone Core
R. Takagi, Tetrahedron Letters, 45, 2004, 7401-7405.
O
R1
R2
R3CO2R K2CO3, TBAB
solvent
O
R3
R2 R1
RO2C
O
R3
R2 R1
RO2C
R3
R1
RO2C
O
R2
14 15
16
Entry Subst. K2CO3 (equiv)
TBAB (equiv)
Solvent Conditions Product (isolated yield)
1 R2, R3 = MeR = Et
3.0 1.0 Toluene 80 oC, 6h 65: 13: 4
2 R2, R3 = MeR = PhCH2CH2
2.0 1.0 Toluene 90 oC, 9h 49: 13: 6
3 R2, R3 = MeR = t-Bu
3.0 1.0 THF 90 oC, 23h 91: 0: 0
4 R1 = OEtR2 = MeR3 = H
2.0 1.0 Toluene 80 oC, 54h 41: 0: 0
5 R1 = OEtR2 = HR3 = CO2Et
3.0 1.0 THF 80 oC, 24h 17: 17: 48
1818
Miesch New Cascade Reactions Miesch New Cascade Reactions Starting from Acetylenic Starting from Acetylenic -ketoesters-ketoesters
O
O
O
E
n
O
n
i) (CH3)2NNH2, CF3COOH cat. C6H6, reflux
ii) n-BuLi, THF, -5 oC, 5-iodopentyne
O
n
E
iii) diethyleneglycol, p-TsOH cat., C6H6, refluxiv) n-BuLi, THF, -78 oC, ClCO2Et, HCl 10%
n=1 overall yield 51%n=2 overall yield 50%
M. Miesch, Tetrahrdron Letters, 44, 2003, 4483-4485.
1919
Miesch New Cascade Reactions Miesch New Cascade Reactions Starting from Acetylenic Starting from Acetylenic -ketoesters-ketoesters
O
E
M. Miesch, Tetrahrdron Letters, 44, 2003, 4483-4485.
C
E
OH
H
E
O
O
O
EE
5% 29%
45% 9%
t-BuOK, THF, -78 oC, 30 min
t-BuOK, THF, 50 oC, 30 min
t-BuOK, THF, 20 oC, 30 min
10%
t-BuOK, THF, 20 oC, 30 min
50%
What is the mechanism???
2020
Stoltz Progress Toward the Stoltz Progress Toward the Synthesis of Synthesis of Garsubellin A Garsubellin A
B. M. Stoltz, Organic Letters, 4, 11, 2002, 1943-1946.
H3C O
O
O O
HOH
H3C
R2
OR
R1
O
Cl
O
Cl
O
O 1. LDA, THF, -78 oC
2.
-78 oC @ 23 oCBr
99% yield
O
O 1. CH3Li, THF, 0 oC
2. 1.0 M HCl, 0 oC
88% yield
O
Et2O, -5 oC
97% yield
Me2CuLiO
NaI, CH3CN, 80 oC
98% yield
TBSCl, Et3NOTBS
2121
Stoltz Progress Toward the Stoltz Progress Toward the Synthesis of Synthesis of Garsubellin A Garsubellin A
OTBSO O
Cl ClCH2Cl2, -10 oC, 11 h
2. KOH (6 equiv) BnEt3NCl, H2O -10 oC @ 23 oC
O
95% combined yield
OH
O
H3C
O
H3C
59% yield 36% yieldsingle diastereomer
OHp-TSA, PhH, 80 oCDean Stark, 10h75% yield
O
O
H3C
O
H3CO
O
H3C
O
H3C
1. Toluene, 140 oC, 7 h
2. CH2N2, Et2O62% yield
Grubbs I(10 mol% )
O
OH3C
O
H3C
B. M. Stoltz, Organic Letters, 4, 11, 2002, 1943-1946.
2222
Nicolaou Synthesis of a Fully Nicolaou Synthesis of a Fully Fonctionalized Bicyclic CoreFonctionalized Bicyclic Core
2323
Nicolaou Synthesis of a Fully Nicolaou Synthesis of a Fully Fonctionalized Bicyclic CoreFonctionalized Bicyclic Core
K.C. Nicolaou, J . Am. Chem. Soc., 121, 1999, 4724-4725.
2424
Nicolaou Synthesis of a Fully Nicolaou Synthesis of a Fully Fonctionalized Bicyclic CoreFonctionalized Bicyclic Core
K.C. Nicolaou, J . Am. Chem. Soc., 121, 1999, 4724-4725.
2525
NicolaouNicolaouHighly Functionalized Medium-Sized RingsHighly Functionalized Medium-Sized Rings
K.C. Nicolaou, ACIE, 44, 2005, 3895-3899.
2626
Shibasaki Retrosynthetic Analysis Shibasaki Retrosynthetic Analysis
OO
OOH O Stille
CouplingO
O
OOH O
I
OHO
OOH O
HO
Wackeroxidative cyclization
RCM
OO
O O
MOMO
O
Claisenrearr.
OO
O O
MOMO
O
Aldol cond.
OOTIPS
MOMO
O
M. Shibasaki, J . Am. Chem. Soc., Vol. 27, No. 41, 2005, 14200-14201.
2727
Shibasaki Synthesis of (±)-Garsubellin A Shibasaki Synthesis of (±)-Garsubellin A
O O
R
OO
O
X
CHO
Intramolecular Aldol Strategy
X
R=H
R = prenyl
O O
R
OO
O
X
OH
2828
Shibasaki Synthesis of (±)-Garsubellin A Shibasaki Synthesis of (±)-Garsubellin A
O
OEt
a, b
100%
O
c 61%
d 92%
O OTIPS
Aldol anti:syn, 50:12 isomers 4:1
e 73%f 96%
g 98%
O
MOMO
OTIPS
a. LDA; prenyl bromide, Bu4NIb. MeLi.LiBr; HCl
c. MeMgBr, CuI (22 mol% ); i-PrCHOd. TIPSOTf, 2,6-lutidine
e. PhSiH3, Co(acac)2 (20 mol% ), O2f. MOMCl, i-Pr2NEt, Bu4NIg. KHMDS, prenylbromide, Bu4NI
h 94%i 98%
O
MOMO
OTIPS
h. LDA, TMEDA; CH3CHOi. Martin sulfurane
j, k 30%
O
MOMO
OTIPS
O
O
O
j. AD-mix-(0.4 mol% of Os), CH3SO2NH2 1:1 mixturei. Triphosgene, pyridine; separation
Mukaiyama hydration
2929
Shibasaki Synthesis of (±)-Garsubellin A Shibasaki Synthesis of (±)-Garsubellin A
l, m 70%n 82%
O
MOMO
O
O
O
O
l. HF.pyridinem. PDC, Celiten. NaHMDS, MS 4A, ethylene carbonate, allyl iodide
O
MOMO
O
O
O
O
o. NaOAc, 200 oC
p 92%
O
MOMO
O
O
O
O
p. Grubbs-Hoveyda (20 mol% )
q, r 70%
O
HO
O
O
O
O
O
q. (PhSe)2, PhIO2, pyridiner. CSA
3030
Mechanism of the Wacker Oxidation: Mechanism of the Wacker Oxidation:
R
Pd Cl
Cl O
HH
R
PdCl-
ClOH
R
OH
RPd(0)
H+ + 2 Cl- +
2 CuCl2 2 CuCl
1/2 O2 + 2 HCl
+ H2OPdCl2
Catalytic cycleLow Cl- concentration
Pd Cl-
Cl H
RHO
Pd Cl-
Cl OH
R
H+
H2O +
-Hydride
Rate determining step
Hamed, O.; Thompson, C.; Henry, P. M. J. Org. Chem. 1997, 62, 7082.Hamed, O.; Thompson, C.; Henry, P. M. J. Org. Chem. 1999, 64, 7745.
3131
Shibasaki Synthesis of (±)-Garsubellin A Shibasaki Synthesis of (±)-Garsubellin A
s, t 71%
O
HO
O
HO
OO
s. LiOHt. PdCl4, TBHP
u, v 80%
O O
HO
OO
u. I2, CANv. p-TsOH.H2O
I
w 20%
O O
HO
OO
w. PdCl2.dppf, tributyl prenyl tin
23 steps synthesis
overall yield: 0.43%
M. Shibasaki, J . Am. Chem. Soc., 127, 2005, 14200-14201.M. Shibaski, Org. Lett., Vol. 6, No. 23, 2004, 4387-4390.M. Shibasaki, Org. Lett., Vol. 4, No. 5, 2002, 5225-5236.M. Shibasaki, Tetrahedron Letters, 43, 2002, 3621-3624.
