total synthesis proposal of phaeospelide-a...the total synthesis of the oxopolyenemacrolide rk-397....
TRANSCRIPT
Presenter: Jiaojiao Wang04/18/2020 1
Total Synthesis Proposal of Phaeospelide-A
O
O
HO
OH OH OH OH OH
2
1. Phaeospelide-A is an important fungal natural product, a secondaryMetabolites of Arthrinium phaeospermum.
2. Fungal secondary metabolite, Phaeospelde-A, remains an attractive source for drug discovery.
3. First isolated by Yohei Morishita, Huiping Zhang, Tohru Taniguchi, Keiji Mori, Teigo Asai in 2019
1. Morishita, Y.; Zhang, H.; Taniguchi, T.; Mori, K.; Asai, T., The Discovery of Fungal Polyene Macrolides via a Postgenomic Approach Reveals a Polyketide Macrocyclization by trans-Acting Thioesterase in Fungi. Org. Lett. 2019, 21 (12), 4788-4792.
3
O
O
HO
OH OH OH OH OH
olefin metathesis
macrolactonization
OH
GPO
OPG OPG OPG OPG OH
enantioselective reductive coupling
O
OH
horner-wadsworth-emmons reaction
horner-wadsworth-emmons reaction
4
O
OH
O
H (MeO)2PO
CO2Me
horner-wadsworth-emmons reaction
EtO
O
O
O
5
OH
GPO
OPG OPG OPG OPG OH
enantioselective reductive coupling
horner-wadsworth-emmons reaction
O
ClOH
ClO
ClO OH
OHO
PO
OO
OCl
PO
OO
O
HOOHO
OCl
O
HO
6
1. Kiran, Y.; Wakamatsu, H.; Natori, Y.; Takahata, H.; Yoshimura, Y., Design and synthesis of a nucleoside and a phosphonate analogue constructed on a branched-threo-tetrofuranose skeleton. Tetrahedron Lett. 2013, 54 (30), 3949-3952.2. Ravikumar, V. T.; Cheruvallath, Z. S., A Convenient Large Scale Synthesis of 4-Cyano-2-butene-1-ol. Synthetic communications 1996, 26 (9), 1815-1819.3. Heckenbichler, K.; Schweiger, A.; Brandner, L. A.; Binter, A.; Toplak, M.; Macheroux, P.; Gruber, K.; Breinbauer, R., Asymmetric reductive carbocyclization using engineered ene reductases. Angew. Chem. Int. Ed. 2018, 57 (24), 7240-7244.
HOOH OH
HOLiAlH4
THF, 0 °C
ClHO
SOCl2, PyridineEt2O
ClMnO2
CH2Cl2
10$/25g
O
7
OClO
O
Cl
HO
OH
2-Deoxyribose-5-phospate aldolase
pH 6.2, 37 °C
2,2-methoxypropene
PPTS (cat.)
O
O OCl
OHHO
TMSOTf (cat.)
O OCl
O
OSi O S
O
OCF3
TMSOTf
150$/1Kg23$/25g
1. Ošlaj, M.; Cluzeau, J.; Orkić, D.; Kopitar, G.; Mrak, P.; Časar, Z., A highly productive, whole-cell DERA chemoenzymatic process for production of key lactonized side-chain intermediates in statin synthesis. PLoS One 2013, 8 (5).
81. Quintard, A.; Rodriguez, J., Enantioselective Ir-Catalyzed Bidirectional Reductive Coupling. Org. Lett. 2018, 21 (2), 453-456.
O OCl
O
O Cl O O
O
O OHCl
(R)-Ir-cat.2 (5 mol %)K3PO4
(2.2 equiv)
i-PrOH, THF,60 °C
O
OO
O
P
P
Ph Ph
PhPh
Ir O O
NO2
O
As the reference discussed, R-catalyst gives R chiral center alcohol product, S-catalyst gives s chiral center alcohol product.
9
ClO
OHO
Cl(S)-Ir-cat.2 (5 mol %)K3PO4
(2.2 equiv)
i-PrOH, THF,60 °C
PO
OO
NaH
THFCl
OH
O
O
1. Ponpandian, T.; Muthusubramanian, S., A new method of synthesising (±)-thalictroidine and (±)-hygrine. Tetrahedron Lett. 2011, 52 (13), 1520-1522.
10
O O
O
O OHCl
(R)-Ir-cat.2 (5 mol %)K3PO4
(2.2 equiv)
i-PrOH, THF,60 °C
O O
O
O OH OH OHCl
ClOH
O
1. Quintard, A.; Rodriguez, J., Enantioselective Ir-Catalyzed Bidirectional Reductive Coupling. Org. Lett. 2018, 21 (2), 453-456.
111. Sartor, M.; Stein, T.; Hoffmann, F.; Froba, M., A New Set of Isoreticular, Homochiral Metal–Organic Frameworks with ucp Topology. Chemistry of Materials 2016, 28 (2), 519-528.
OHOO Cu, cat.1
CH2Cl2
OH
HN
OO
O
OCu
H2O
O O
O
OCu
OH2
Cat.1
121. Quintard, A.; Rodriguez, J., Enantioselective Ir-Catalyzed Bidirectional Reductive Coupling. Org. Lett. 2018, 21 (2), 453-456.
O O
O
O OH OH OHCl
OHO(R)-Ir-cat.2 (5 mol %)K3PO4
(2.2 equiv)
i-PrOH, THF,60 °C
HCl
MeOH
OH OH OH OH OHCl
TBSClimidazole
TBSOTBSO OTBS OTBS OTBSCl
TBSO
OTBS OTBS OTBS OH OHTBSO
O
O
O
131. Ghorbani-Vaghei, R.; Shahbazee, E.; Veisi, H., N, N’-Diiodo-N, N’-1, 2-ethanediylbis (p-toluenesulfonamide) as a reagent for conversion of aldehydes to methyl esters. Mendeleev Communications 2005, 5 (15), 207-208.
TBSO
OTBS OTBS OTBS OH OHTBSO O
TBSO
OTBS OTBS OTBS OH OHTBSO
PO
OO
NaH
THF
14
O
O
NaH
EtO
OPO
(OEt)2
H
O
H
O1. DIBAL-H
AlH
HAl
2.IO
O
AcO OAcOAc
EtO
O
1. Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T., The Total Synthesis of the Oxopolyene Macrolide RK-397. Angew. Chem. Int. Ed. 2007, 46 (7), 1066-1070.
15
O
O 1. DIBAL-H
2. Dess MartinPeriodinane
OI
O
O OO O
OO
Al HH Al
O
H
1. Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T., The Total Synthesis of the Oxopolyene Macrolide RK-397. Angew. Chem. Int. Ed. 2007, 46 (7), 1066-1070.
16
TBSO
OTBS OTBS OTBS OH OHTBSO
H
O
RuPPh3
PPh3
PhClCl
CH2Cl2, reflux
TBSO
OTBS OTBS OTBS OH OHTBSO O
1. Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T., The Total Synthesis of the Oxopolyene Macrolide RK-397. Angew. Chem. Int. Ed. 2007, 46 (7), 1066-1070.
17
O
O(MeO)2P
O
CO2MeNBS
O
O
Br(MeO)3P
1. Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T., The Total Synthesis of the Oxopolyene Macrolide RK-397. Angew. Chem. Int. Ed. 2007, 46 (7), 1066-1070.
18
TBSO
OTBS OTBS OTBS OH OHTBSO O
(MeO)2PO
LDA
TBSO
OTBS OTBS OTBS OH OHTBSO
OMe
O
CO2Me
1. Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T., The Total Synthesis of the Oxopolyene Macrolide RK-397. Angew. Chem. Int. Ed. 2007, 46 (7), 1066-1070.
19
O
O
TBSO
TBSO OTBS OTBSTBSO OH
1. LiOH, THF/H2O/MeOH
2. 2,4,6-trichlorobenzoyl chloride Et
3N3. DMAP, Toluene
TBSO
OTBS OTBS OTBS OH OHTBSO
OMe
O
1. Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T., The Total Synthesis of the Oxopolyene Macrolide RK-397. Angew. Chem. Int. Ed. 2007, 46 (7), 1066-1070.
20
O
O
HO
OH OH OH OH OH
O
O
TBSO
TBSO OTBS OTBS OTBSOH
HCl, MeOH
1. Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T., The Total Synthesis of the Oxopolyene Macrolide RK-397. Angew. Chem. Int. Ed. 2007, 46 (7), 1066-1070.
Thank you!
21