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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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

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(+)-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

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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

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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

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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

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Tandem Transannular Diels-Alder Reactions

TESO OTESO

OTMS

Ot-Bu

O

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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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R2Ot-BuOO

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OTESH

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i. PPTS, MeOHii. TFA/CH2Cl2 (1:9), 0°C O

HO

H

H

H

HOHOO

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H

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OHH

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EDC, DMAP, CH2Cl2O

HO

H

H

H

O

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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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(+)-FR182877 (-)-FR182877

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OH

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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