enantioselective total synthesis of (+)-wortmanninccc.chem.pitt.edu/wipf/current...
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EnantioselectiveTotalSynthesisof(+)-Wortmannin
JohnMilligan CurrentLiteratureWipf GroupMeeting June10,2017
1
Guo,Y.;Quan,T.Lu,Y.;Luo,T.J.AmChem.Soc.2017,139,6815-6818
O
O
H
OOO
MeO AcO
(+)-wortmannin
Wortmannin• Firstisolatedin1957,butstructurenotconfirmeduntiltheearly1970’s• Potent(IC50 =5nM)inhibitorofphosphatidylinositol3-kinase(PI-3K),whichispartofasignalingcascadeforcellgrowthanddifferentiation
2
Wipf,P.;Halter,R.J.Org.Biomol.Chem.2005,3,2053-2061.
Mechanismofaction
3
O
O
H
OOO
MeO AcO
(+)-wortmanninNH2
Lys802
O
O
HOO
MeO AcO
NH
Lys802
irreversiblecovalent PI3K
inhibition
OH
• Strained(12kcal/mol)andelectrophilicfuranmotifallowsforcovalentattachmentofLys-802onPI-3K
Wipf groupcontributions
4
Ihle,N.T.;Paine-Murrieta,G.;Berggren,M.I.;Baker,A.;Tate,W.R.;Wipf,P.;Abraham,R.T.;Kirkpatrick,D.L.;Powis,G.Mol.CancerTherap.2005,4(9),1349-1357.
O
O
H
OOO
MeO AcO
(+)-wortmannin
O
O
H
OHOO
MeO AcO
PX-866
N
•IC50 of against purified PI3K: 0.1 nM•more stable in vivo•decreased toxicity
furan cleavage
PreviousTotalSyntheses
5
O
OH
H
OOO
MeO AcO
(+)-wortmanninO
HO O
H
OHH
HO
hydrocortisone
24 steps
O
OH
HMeO
OBz
O11 steps
1st generation:
2nd generation:
O
O
Hajos-Parrish ketone
OO
TfO H
SEMO
BnO
Pd(OAc)2 (10 %)dppp, K2CO3
Bu4NBr
toluene, 100 °C65%
OO
H
SEMO
BnO
31 steps
Sato,S.;Nakada,M.;Shibasaki,M.TetrahedronLett.1996,37,6141-6144.Mizutani,T.;Honzawa,S.,Tosaki,S.;Shibasaki,M.Angew.Chem.Int.Ed.2002,41,4680-4682
Titlepaper:retrosynthesis
6
O
O
H
OOO
MeO AcO
(+)-wortmannin
O
OTBS
OOO
MeO
C-H oxidation
OH
HO
OTBS
OO
MeO
lactone formation
HH
HO
OTBS
O
MeO
HH
Friedel-Crafts
Stille
Alkylation
O
O
Hajos-Parrish ketone
XOTBSOTBSO
HO SnBu3
FuranSynthesis
7
CarboxylationwithMMC:Frie,J.L.;Jeffrey,C.S.;Sorensen,E.J.Org.Lett.2009,11,5394.
O(2 steps from
Hajos-Parrish ketone)
MeO MgO OMe
O
DMF, 130 °C85% O
CO2H
OBoc
OHHO
OTBS
O
O
HO
OTBS OTBS Pd2(dba)3 (2 mol %)dppf (8 mol %)DIPEA (2.4 eq)
PhCl, 130 °C, 1.5 h42%
HO
(inefficient alkylation,non-trivial preparation of electrophile)
BrOTBSO
FuranSynthesisMechanism
8
Reduction/Coupling
9
HO SnBu3
OTBS
O
O
HO
1. TBSCl, imidazole DMF, 0 °C to rt, 85%
2. NiCl2• 6 H2O, NaBH4 MeOH, –90 to –60 °C 69%
OTBS
O
O
TBSOH
1. LiHMDS; PhNTf2 THF, –78 to 0 °C 98%
2.
Pd2(dba)3, AsPh3NMP, 70 °C, 69%
OTBS
OTBSO
HHO
Epoxidation
10
OTBS
OTBSO
HHO
1. TBHP, Ti(Oi-Pr)4, (–)-DIPT, 4 A MS CH2Cl2, –40 °C, 68%
2. NaH, MeI DMF, 91%
OTBS
OTBSO
HMeO O
IntramolecularFriedel-Crafts
11
OTBS
OTBSO
HMeO O Ph4PBF4 (3 eq)
4:1 CH2Cl2/HFIP–15 °C, 84 h
OTBS
OTBSO
HMeO
OH
TBAF • 3 H2O
THF, rt47% (2 steps)
OTBS
OTBSO
HMeO
OH
(major) (minor)OTBS
OHO
HMeO
OH
OxidationSequence
12
OTBS
OHO
HMeO
OH1. PhI(OAc)2, TEMPO CH2Cl2, rt2. NaClO2, Na2HPO4 2-methyl-2-butene
3. CMPI, Et3N, CH2Cl2 70% (3 steps)
O
OTBS
OO
MeO
HH
1. H2O2•urea TFAA, Na2CO3 CH2Cl2, 0 °C, 69%
2. NBS, AIBN (0.3 eq) CCl4, reflux, then; DMSO, AgBF4, Et3N 65%
O
OTBS
OO
MeO
HHO
O
H
EndGame
13
O
OTBS
OO
MeO
HHO
O
1. Et3N • 3 HF, THF, 45 °C, 95%
2. DMP, CH2Cl2, 89%
O
OO
MeO
HHO
O
O
Et2NH
CH2Cl2, rt
O
O
MeO
HHO
O
O
OHNEt2
O
O
H
OOO
MeO AcO
(+)-wortmannin
DBN, 35 °Cthen 3 M HCl54%
then Ac2Opyridine, 84%
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O
H
O O
(–)-Hibiscone C
O
OH
OO
MeO
HHO
O
O
OH
H
OOO
MeO AcO
O
O
H
OOO
MeO AcO
(+)-Wortmannin
Conclusions• Thetotalsynthesisof(+)-wortmanninwascompletedin21stepsand0.4%overallyeildfromtheHajos-Perrishketone• KeyfeaturesincludeanovelPd-mediatedfuransynthesis,intramolecularFriedel-Craftsalkylation,andlatestageformalC-Hoxidation• Kinaseprofilingofsyntheticwortmanninandrelatedanalogswasconducted
15
16
HO H
HH
O
Ph4PBF4
HFIP, 0 °C, 5 min56%
Tian,Y.;Xu,X.;Zhang,L.;Qu,J.Org.Lett.2016,18,268-271.