Post on 09-Feb-2016
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Sorensen’s Enantioselective Total Synthesis of FR182877
Presented byBriAnne Bentivegna
Vanderwal, C.D.; Vosburg, D.A.; Weiler, S.; Sorensen, E.J. J. Am. Chem. Soc. 2003, 125, 5393
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OHH
HO
Erik J. Sorensen• B.A. in Chemistry from Syracuse University (1989)
– Researched under Roger Hahn• PhD from K. C. Nicolaou at the University of
California, San Diego (1995)• Post Doctoral Fellow with Samuel Danishefsky at The
Memorial Sloan-Kettering Cancer Center in New York (1995-1997)
• Began his independent career at The Scripps Research Institute (1997)– Achieved Tenure (2001)
• Moved to Princeton University (2003)– Arthur Allan Patchett Professor in Organic
Chemistry• Awards: Arthur C. Cope Scholar Award from ACS,
Pfizer Global Research Award for Excellence in Organic Chemistry, Woodward Scholar at Harvard University, Beckman Young Investigator Award and many more 2http://www.princeton.edu/~ejsgroup/ejs.html
FR182877 • Isolated from the fermentation broth of Streptomyces sp. No9885 in 1988• Constitution and relative stereochemistry determined by NMR and X-ray
crystallography• Absolute stereochemistry determined by advanced Mosher ester analysis
– Initial absolute proposed was (+)-1; later changed to (-)-1• Part of family of secondary metabolites that bind and stabilize cellular microtubules
– Other Members: Taxol, Discodermolide, Epothilones • Shown to have similar activity to Taxol
– Potential as chemotherapeutic agent • Has 12 stereocenters and strained bridgehead olefin that’s part of carbonate moiety • Synthesized because of its biological activity and reactivity of its strained olefin
3H. Muramatsu, M. Miyauchi, B. Sato, S. Yoshimura, 40th Symposium on the Chemistry of Natural Products (Fukuoka, Japan), 1998, Paper 83, p. 487
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HODiscodermolideFR182877
Epothilone A
Taxol
Images Source: Wikipedia
Retro Synthesis of FR182877
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OHH
HO
(+)-FR182877
Tadam T.A.D.A.TESO OTES O
OTMS
O t-BuO
Tsuji-TrostOTES
OTESTESO
NOMe
OO
-allyl Stille Coupling
OTESSnMe3
OTESTESO
HWETBSOO O
Me
PO
OMeOMe
HMe
I
O
+ON
O O
Bn
+ TBSO H
O
+
NOMe
OAc
OO
AcOH
OON
O O
Ph
+
TMS
TMS
TMS
The Beginning
5
ON
O O
Bn
+ TBSO H
O n-Bu2BOTf, Et3N CH2Cl2, 0°C
TBSOOH
N O
O O
BnMe
TBSOOH
N
O
Me
OMe
Me
i.TMSCl, imidDMAP, CH2Cl2
ii. LiCH2P(O)(OMe)2 THF, -78°C
TBSOO O
Me
PO
OMeOMe
HOI
OOH
Me
TESOI
O
Me
OTESi. Et2BOMe, NaBH4THF/MeOH, -78°Cii. TESCl, imidazole
DMAP, CH2Cl2
Me3SnSnMe3, Pd(Ph3P)4,i-Pr2NEt, PhH, 80oC
TESOSnMe3
O
Me
OTES
i. Ba(OH)2, THF then (E)-ß-iodomethacrolein,
THF/H2O, 0°Cii. PPTS, MeOH
MeONHMe·HCl, Me3AlTHF, 0°C
43 44
45 46
47
TBS
TES
TES
Weinreb
Horner-Wadsworth-Emmons
I O
(E)-ß-iodomethacrolein
SO3
NH
PPTS
Hϋnig’s Base
Synthesis of 19-Membered Macrocycle
6Canonica, L.; Rindone, B.; Santaniello, E.; Scolastico, C. Tetrahedron 1972, 28, 4395
OTESSnMe3
OTESTESO
47
NMe
O
NMP
NOMe
OAc
OO
i. n-Bu2BOTf, Et3N CH2Cl2, 0°C
ii. MeONHMe·HCl, Me3Al,THF, 0°C
iii. TMSCl, imid, DMAP,CH2Cl2
AcOH
O
ON
O O
Ph
+
"Known Aldehyde"55
47, Pd2dba3, i-Pr2NEt,LiCl, NMP, 40°C
OTES
OTESTESO
NOMe
OO
i. LDA, t-BuOAc, THF, -78°Cii. TBAF, THF, -30°C
OH
OTESTESO
OOH
i. MeOCOCl, pyr, CH2Cl2ii. TMSCl, imid, CH2Cl2
56 57O
Ot-Bu
O
OTESTESO
OO
58O
Ot-Bu
O
OMe1
19
Pd2dba3, THF (0.005 M), 40°C
TESO OTES OOTMS
O t-BuO
19
1
59
TMS
TMS
TMS
-allyl Stille Coupling
Tsuji-Trost
Hϋnig’s Base
7
Tandem Transannular Diels-Alder Reactions
TESO OTESO
OTMS
Ot-Bu
O
59
KHMDS, PhSeBr,THF, -10°C
TESO OTESO
OTMS
Ot-Bu
O
60
PhSemCPBA, CH2Cl2
-78°C
TESO OTESO
OTMS
Ot-Bu
O
61E
NaHCO3, CHCl340°C, 4h O
TESO
H
H
H
R2Ot-BuOO
H
H
H
OTESH
62
H
R=TMSTandem Transannular
Diels Alder
7 NEW STEREOCENTERS FORMED!!!
The Final Steps!
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TESO
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R2Ot-BuOO
H
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H
OTESH
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i. PPTS, MeOHii. TFA/CH2Cl2 (1:9), 0°C O
HO
H
H
H
HOHOO
H
H
H
OHH
65
EDC, DMAP, CH2Cl2O
HO
H
H
H
O
H
H
H
OHH
H H
HO
(+)-1: (+)-FR182877
R=TMS
N
N
CN
EDC
2.09% Yield 22 Linear Steps
Large Scale Synthesis of the 19-Membered Macrocycle
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Used opposite enantiomers of small scale synthesis since it was found that the initially assigned absolute stereochemistry was incorrect!
Large Scale Synthesis of (-)-FR182877
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a (a) NaHMDS, PhSeBr, <1 min, 23 °C, 89%, 10:1 dr. (b) mCPBA, CH2Cl2, -78 °C. (c) NaHCO3, CHCl3, 45 °C, 4 h, 61-66% of ent-62 over two steps (8-15% each of 63 and 64 also isolated). (d) PPTS, MeOH, 0 f 23 °C, 100%. (e) TFA/CH2Cl2 (1:9), 0 f 23 °C, 96%. (f) N-methyl-2-chloropyridinium iodide, Et3N, CH2Cl2/MeCN (9:1), 23 °C, 60% + 21% recovered starting material.
Conclusion
• Both (+)-FR182877 and (-)-FR182877 were synthesized
• (-)-FR182877, the natural enantiomer, was synthesized on a large scale yielding 100 mg
• There are 22 linear steps with 2.09% yield
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OHH
HO
(+)-FR182877 (-)-FR182877
O
OH
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O
H
H
H
HOH
H O
Synthesis of “Known Aldehyde”
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AcONBS, tBuOH AcO
OHBr
K2CO3, MeOH
HOO
i. MeOCOCl, pyr, CH2Cl2ii. HClO4, diglyme AcO
OHOH
NaIO4, THF AcOO
H
OO
O
Diglyme
Canonica, L.; Rindone, B.; Santaniello, E.; Scolastico, C. Tetrahedron 1972, 28, 4395