A Concise, Efficient, and Scalable Total Synthesis ofThapsigargin and Nortrilobolide from (R)-(-)-Carvone

Dezhi Chen and P. Andrew EvansJ. Am. Chem. Soc. 2017, 139, 6046.

Evan CarderWipf Group Current Literature

June 24, 2017 06/24/17 1

H

OMe

HO

O

O

OHMe

Me O

O

Me

OPr

OO

OMe

6OMe

Me

Thapsigargin

Me

HH

O

(R)-(-)-Carvone

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Origins of Thapsigargin

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1. Acta Pharm. Suec. 1978, 15, 133.2. J. Org. Chem. 1982, 47, 649.3. Tetrahedron Lett. 1985, 26, 107.

§ Associated in folk medicine

§ Isolated from the roots of Thapsiagarganica L. in 1978 by Christensen and coworkers.1

§ Chemical structure was elucidated by extensive spectroscopic studies and X-ray crystallography.2,3

§ A member of 17 structurally-related sesquiterpenones, which are collectively known as thapsigargins.

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Structural Features of Thapsigargin

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§ 5-7-5 tricyclic core

§ Eight stereogenic centers

§ Polyoxygenated

§ Functionalized with four different ester groups

§ Thapsgargins primarily differ in the acyl groups appended to O-2 or O-8.1

§ Three distinct syntheses have been reported: Steven Ley2, Phil Baran3, and P. Andrew Evans4

H

OMe

HO

O

O

OHMe

Me O

O

Me

OPr

OO

OMe

6OMe

Me

23

6 7

8

110

11

Thapsigargin

1. Chem. Eur. J. 2007, 13, 5688.2. Angew. Chem., Int. Ed. 2003, 42, 5996.3. ACS Cent. Sci. 2017, 3, 47.4. J. Am. Chem. Soc. 2017, 139, 6046.

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Biological Relevance of Thapsigargin

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§ Extensive biological evaluation

§ Selective, sub-nanomolar inhibitor of sarco/endoplasmic reticulum calcium ATPase (SERCA)-dependent pumps.1,2

§ Binds to SERCA and induces a conformation that deters calcium and ATP binding.1,2

§ Treatment severely alters cellular calcium concentrations, leading to disrupted cell growth and programmed cell death.3,4

§ Promising therapeutic potential 1. J. Biol. Chem. 1991, 266, 13503.2. J. Biol. Chem. 1995, 270, 11731.3. J. Biol. Chem. 1994, 269, 11927.4. Prostate 1997, 80, 201.

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Total Synthesis by the Steven Ley Lab

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Angew. Chem., Int. Ed. 2003, 42, 5996.Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12073.Chem. Eur. J. 2007, 13, 5688.Org. Lett. 2007, 8, 2879.

Me

H

O

(S)-(+)-Carvone

H

O

ClMe

THPOTBDPSO

H

CO2MeH

Favorskii ringcontraction

3-steps 3-steps

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Ley Lab

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TBDPSO

H

CO2MeH

TBDPSO

H

H

Me OMOM

OEtTESO

9-steps TBDPSO

H

H2-steps

OTESO

Me OMOM

OH

enol etherring closing methasis

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Ley Lab

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TBDPSO

H

H OTESO

Me OMOM

OH 2-steps TBDPSO

H

HTESO

Me OMOM

OO

Me

9-steps O

H

H

Me OH

O

OO

HO

OMe

Dihydroxylation; translactonization

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Ley Lab

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O

H

H

Me OH

O

OO

HO

OMe

14-steps OMe

HMe OAc

OPrOO

O

Me6

HO

OO

OHMe

Thapsigargin42-steps, 0.61% overall yield

O

MeMe

late-stage a-oxidation;regioselective acylations

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Toward the Synthesis by the Guillermo Massanet Lab

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O1. KOH, O2

MeOH, rt, 48 h

70%(+)-Dihydrocarvone

Me

MeOMe

+ Me

Me

OMe OH

2. DDQ, 1,4-dioxane

refluxing, 20 h

85%

Me

Me

OMe OH

RobinsonAnnulation

Org. Lett. 2006, 8, 2879.

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Massanet Lab

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3. Burgess reagent

PhH, rt-50 oC, 5 hMe

Me

OMe OH

Me

OMe

98%

4. AD-mix-a

tBuOH, H2O 0 oC, 15 h

Me

OMe OH

OHMe

76%

AD-mix-a

§ K2OsO4 2H2O§ K3Fe(CN)4§ K2CO3§ (DHQ)2PHAL

Burgess Reagent

O N-O

S N+O O

Sharpless assymetricdihydroxylation

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Massanet Lab

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Me

OMe OH

OHMe

5. hv

1:1 AcOH: H2O rt, 2.5 h

93%

O

Me

H

OH

OHMe

Me OAc

6. OsO4, NMO, CH3SO2NH2

tBuOH/H2O/acetone 0 oC-rt, 24 h

O

Me

H

OH

OHMe

Me OAc

HO

HO

61%

J. Chem. Soc. 1957, 929.

Me

OMe

hv

AcOH

30-38%

O

Me

HMe OAc

O O

HMe H

MeO O

Precedence:

Me

OMe

hv

AcOH

39%

O

Me

HMe OAc

O O

HMe H

MeO O

J. Chem. Soc. 2005, 127, 18.

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Massanet Lab

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7. TEMPO, NaClO, NaClO2

MeCN, pH 7 buffer rt, 4 h

98%7,11-Dihydoxyguaianolide

O

Me

H

OH

OHMe

Me OAc

HO

HO O

Me

HMe OAc

HO

OO

OHMe

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Total Synthesis by the Phil Baran Lab

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RobinsonAnnulation

O

1. KOH, MeOH 0 oC - rt, 15 h rt - 65 oC, 3.5 h

then O2, rt, 12 h

50%[gram-scale]

(+)-Dihydrocarvone

Me

MeOMe

+ Me

Me

OMe OH

2. TMSOTf, Et3N CH2Cl2, 0 oC, 2.5 h

then NBS, 0 oC, 3 h then DBU, 50 oC, 18 h then HCl, rt, 5 h

85%[gram-scale]

Me

Me

OMe OH

ACS Cent. Sci. 2017, 3, 47.

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3. Burgess reagent DCE, 80 oC, 5.5 h then AD-mix-B tBuOH, H2O 0 oC, 24 h

[gram-scale]

Me

Me

OMe OH

Me

OMe OH

OHMe

60% dr. 5:1

4. TBSCl, Imidazole THF, rt, 24 h

then SeO2, NaHCO3 dioxane, 105 oC, 24 h

[gram-scale]

Me

OMe OTBS

OHMe

52% dr. 5:1

OH

Baran Lab

Sharpless assymetricdihydroxylation

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5. PBu3, DEAD butyric acid

THF, 0 oC - rt, 16 h

[gram-scale]

Me

OMe OTBS

OHMe

OH Me

OMe OTBS

OHMe

O

PrO

60% dr. 5:1

6. AcOH, hv

rt, 23 h

[gram-scale] 50%

O

Me

H

OTBS

OHMe

Me OAc

OPrO

Baran Lab

MitsunobuReaction

Precedence:

Org. Lett. 2006, 8, 2879.

Me

OMe OH

OHMe

hv

1:1 AcOH: H2O rt, 2.5 h

93%

O

Me

H

OH

OHMe

Me OAc

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7. KMnO4, octanoic acid octanoic anhydride

benzene, 85 oC, 20 h

[gram-scale] 50%

O

Me

H

OTBS

OHMe

Me OAc

OPrO

O

Me

H

OTBS

OHMe

Me OAc

OPrOO

O

Me6 8. OsO4, NMO, citric acid

tBuOH/H2O/acetone (1:1:1) 50 oC, 13 h

[gram-scale]33%, R = H23%, R = TBS

O

Me

H

OR

OHMe

Me OAc

OPrOO

O

Me6

HO

HO

Baran Lab

Upjohn dihydroxylation

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9. Py SO3, pyridine DIPEA, DMSO CH2Cl2, 0 oC, 0.5 h

[gram-scale]

O

Me

H

OH

OHMe

Me OAc

OPrOO

O

Me6

HO

HO O

Me

HMe OAc

OPrOO

O

Me6

HO

OO

OHMe

43%

10. Zn(BH4)2, Et2O

-20 oC, 4 hHO

Me

HMe OAc

OPrOO

O

Me6

HO

OO

OHMe

88%

Baran Lab

Parikh-DoeringOxidation

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Baran Lab

11. PhCOCl, Et3N angelic acid, toluene

90 oC, 72 hHO

Me

HMe OAc

OPrOO

O

Me6

HO

OO

OHMe

88%

OMe

HMe OAc

OPrOO

O

Me6

HO

OO

OHMe

59%Thapsigargin

11-steps, 0.137% overall yield

O

MeMe

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Me

HH

O

1. tBuOCl, SiO2 pentane, rt, 12 h

2. Dibal-H, CH2Cl2 -78 oC, 0.5 h; then TBSCl, imidazole -78 oC - rt, 12 h

Me

ClH

OTBS

88% (two steps)dr > 19:1

Me

H

OTBS

E = CO2Me93%

dr > 8:1

OBnO

EOTMSMe

3. Pd2(dba)3 CHCl3 (S)-BINAP, LiCl THF, 0 oC, 0.5 h

then LiHMDS, 9 THF, 0 oC, 36 h

[gram-scale]

[gram-scale]

BnOO

CO2MeTMSO Me 9

(R)-(-)-Carvone

Current work: P. Andrew Evans LabJ. Am. Chem. Soc. 2017, 139, 6046.

BnOO

CO2MeTMSO Me 9

BnO CO2Me

Me

AD-mix-B, MeSO2NH2

tBuOH, H2O0 oC, 18 h

BnO CO2MeHO Me

OH(COCl)2, DMSOEt3N, CH2Cl2-78-0 oC, 1 h

then TMSCl, imidazole0 oC, 1 h

94% 75%

Synthesis of 9:

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H

OBnO

EOTMSMe [gram-scale]

MeO

TBSOH

OBnMe

TBSOHO

O

O

OTMSMe

5. VCl3(THF)3, Zn HMPA, CH2Cl2, rt

added over 6 h

Guaianolide60%

dr > 19:1

Me

H

OTBS

E = CO2Me

OBnO

EOTMSMe

E = CO2Me40-55%

4. O3, EtOAc, -78 oC then Ph3P, -78 oC rt, 10 h

piperidinium acetate 78 oC, 12 h

[gram-scale]

Evans Lab

PinacolCoupling

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H

OBnMe

TBSOHO

O

O

OTMSMe

Me OH

[gram-scale]

7. Ac2O, DMAP PhMe, 110 oC, 6 h

H

OBnMe

TBSOHO

O

O

OTMSMe

Me O

O

Me

85-96%

H

OBnMe

TBSOHO

O

O

OTMSMe

Guaianolide

[gram-scale]

6. Co(acac)2, PhSiH O2, EtOH, 0 oC, 2 h

79% dr > 19:1

Evans Lab

MukaiyamaHydration

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9. (PrCO)2O, DMAP CH2Cl2, rt, 1h

then CrO3, acetone 0 oC, 5 h

H

OMe

HO

O

O

OHMe

Me O

O

Me

OPr

O

87%

H

OBnMe

TBSOHO

O

O

OTMSMe

Me O

O

Me

[gram-scale]

8. Pd(OH)2/C, H2 EtOAc, rt, 20 min; IBX, DMSO, rt, 12 h

then NaBH4 DMSO/MeOH (1:3) -10 oC, 5 min

94%dr > 19:1

H

OHMe

TBSOHO

O

O

OHMe

Me O

O

Me

Evans Lab

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Evans Lab

61%

11. Zn(BH4)2, Et2O -20 oC, 10 h

12. NaHCO3, 17 PhMe, 90 oC, 45 h

H

OMe

HO

O

O

OHMe

Me O

O

Me

OPr

OO

OMe

6OMe

Me

64%Thapsigargin

12 steps, 5.8% overall yield

O

O

O

ArMe

Me

17Ar = 2,4,6-Cl3C6H2

H

OMe

HO

O

O

OHMe

Me O

O

Me

OPr

O 10. Mn(OAc)3 2H2O C7H15CO2H

benzene, reflux, 4 h

H

OMe

HO

O

O

OHMe

Me O

O

Me

OPr

OO

OMe

6

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Summary

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Total Synthesis: Creighton Lab Baran Lab Evans Lab

Key step(s)Favorskii

Rearrangement, Ring-closing metathesis

Photochemical ring contraction

Asymmetric allyl alkylation, Pinacol

coupling Linear Steps 42 11 12

Overall yield 0.61% 0.14% 5.8%42x

H

OMe

HO

O

O

OHMe

Me O

O

Me

OPr

OO

OMe

6OMe

Me

Thapsigargin

Me

HH

O

(R)-(-)-Carvone

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