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Rychnovsky’s Formal Synthesis of Leucascandrolide A. Presented by BriAnne Bentivegna March 19, 2013 University of Delaware. Kopecky, D.J.; Rychnovsky, S.D. J. Am. Chem. Soc. 2001 , 123 , 8420. Scott D. Rychnovsky. 1981 - B.A. from University of California at Berkeley - PowerPoint PPT Presentation
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Rychnovsky’s Formal Synthesis of Leucascandrolide A
Presented by BriAnne Bentivegna March 19, 2013
University of Delaware
Kopecky, D.J.; Rychnovsky, S.D. J. Am. Chem. Soc. 2001, 123, 8420
O
CH3
O
O
O
OMe
O
O
ON
MeO2CHN
Scott D. Rychnovsky
• 1981 - B.A. from University of California at Berkeley• 1986 - PH.D. from Columbia University • 1987 - NIH Postdoctoral Fellow at Harvard University• 1988 - Faculty member at the University of Minnesota• 1995 - Professor of Chemistry at the University of California – Irvine• Numerous Awards including Arthur C. Cope Scholar Award, Pfizer
Research Award in Synthetic Organic Chemistry and National Science Foundation Presidential Young Investigator Award.
• Associate Editor for The Journal of Organic Chemistry• Research interests include synthesis of rimocidin, phorboxazole A,
epicalyxin F, and leucascandrolide A.2
Leucascandrolide A• First isolated by Pietra and coworkers in 1996 from the
calcareous sponge Leucascandra caveolata along the east coast of New Caledonia
• Displays potent cytotoxic activity in vitro on human P388 (Leukemia) cancer cells as well as antifungal activity
• Synthesized by several groups including the Rychnovsky, Leighton and Kozmin groups
3Dambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. Helvetica Chimica Acta. 1996, 79, 51
Retrosynthesis
4
O
CH3
O
O
OH
OMe
O
O
CH3
O
OH
OTBS
OMe
OH OO
CH3
O
OTBS
OTBS
OMe
O
H
O
CH3
O
OTIPS
OH
OBn
O
OBn
CH3
O
H
+O
TMS
OTIPS
BnO
OTBS
NOHCH3
CH3
CH3
O
BnO OEt
OO
TIPSO OEt
OO
TIPSO
O
H
Noyori Hydrogenation
Noyori Hydrogenation
Yamaguchi-typeCyclization
Aldol - Prins Coupling
BnO OEt
OO [(R)-BINAP]-RuCl(C6H6)8 atm H2, EtOH
BnO OEt
OOH i. TBSCl, imid, DMFii. DIBALH, THF, -25°C
BnO OH
OTBSLDA, (-)-pseudoephendrine propionamide
LiCl then add 15, THF, -78°CPPh3, I2
imid, CH2Cl2BnO I
OTBS
14
15
BnO
OTBS
NOHCH3
CH3
CH3
2N H2SO4dioxane, 95°C
O
O
OBn
OCH3
i. DIBALH, CH2Cl2, -78°Cii. Ac2O, DMAP, pyr
O
OBn
CH3
OAc
AllyltrimethylsilaneBF3·OEt2, CH2Cl2, -78°C
O
OBn
CH3
O3, CH2Cl2,then PPh3, -78°C
O
OBn
CH3
O
H
16
17
14a
14b
15a
16a 16b
Synthesis of Aldo-Prins Precursor #1
5
Noyori Hydrogenation
Synthesis of Aldo-Prins Precursor #2
6
Noyori Hydrogenation
TIPSO
O
HN2CHCO2Et, SnCl2
CH2Cl2 TIPSO OEt
OO[(S)-BINAP]-RuCl(C6H6)4 atm H2, EtOH, 100°C
TIPSO OEt
OOH
18 18a
19
i. TMSCl, Et3N, CH2Cl2ii. CeCl3, TMSCH2MgCl, THF/Et2O, -78°C
iii. SiO2 gel, CH2Cl2TIPSO
OHTMS
20
ClCH2COCl pyr, CH2Cl2 TIPSO
OTMS
20a
OCl
i. DIBALH, CH2Cl2, -78°Cii. Ac2O, DMAP, pyr
TIPSO
OTMS
20b
ClOAc
Li0, NH3
THF, -78°C TIPSO
OTMS
21
Aldol-Prins Coupling
7
Aldol - Prins Coupling
N
O
CH3O
NMO
N N
Proton Sponge
O
OBn
CH3
O
H
17
+
OTMS
OTIPS
21
i. BF3·OEt2, 2,6-di-tert-butylpyridineCH2Cl2, -78°C
ii. NaBH4, EtOH
O
CH3
O
OTIPS
OH
OBn22
MeO BF4, 4 A MSProton Sponge, CH2Cl2
O
CH3
O
OTIPS
OMe
OBn
22a
i. OsO4, NMOii. NaIO4
O
CH3
O
OTIPS
O
OMe
OBn
22b
i. L-Selectride, THF, -90°Cii. TBAF, THF
iii. TBSOTf, 2,6-lutidine, CH2Cl2
O
CH3
O
OTBS
OTBS
OMe
OBn
9
5
23
9
O
CH3
O
OTBS
OTBS
OMe
OBn
23
i. H2, Pd(OH)2, EtOAcii. (COCl)2, DMSO, Et3N
O
CH3
O
OTBS
OTBS
OMe
O
23a
H
17
i. Me2AlCl, tolMe3SnCCCH2CH(CH)3
ii. Red-Al, Et2O
O
CH3
O
OTBS
OTBS
OMe
24
OHi. Ac2O, DMAP, pyr, CH2Cl2ii. Neutral Al2O3, hexanes
O
CH3
O
OH
OTBS
OMe
24a
OAc1
i. (COCl)2, DMSO, Et3Nii. NaClO4, NaH2PO4,
2-methyl-2-butene
O
CH3
O
OH
OTBS
OMe
25
OAc Oi. K2CO3, MeOH
ii. Cl3C6H2COCl, Et3N, DMAP, C6H6iii. HF·pyridine, THF
O
CH3
O
O
OH
OMe
O
Synthesis of Leucascandrolide A Macrolide
8
Leucascandrolide A Macrolide
Yamaguchi-type Cyclization
Final Steps via Leighton
9Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894
O
CH3
O
O
OH
OMe
O (CF3CH2O)2P(O)CH2CO2HEDCI·HCl, HOBt·H2O, CH2Cl2
O
CH3
O
O
O
OMe
O
OP(OCH2CF3)2
O
O
CH3
O
O
O
OMe
O
O
ON
MeO2CHN
ON
MeO2CHN
HO
+
33
KHMDS, 18-crown-6·CH3CN, THF, -100 °C.
3425
Leucascandrolide A!!!
Horner-Wadsworth-Emmons
Conclusion• Leucascandrolide A Macrolide synthesized in 23
steps• Leucascandrolide A synthesized in 25 steps with the
help of Leighton
Questions?
10
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