A Uniﬁed Strategy to ent-Kauranoid Natural Products: Total ...ccc.chem.pitt.edu/wipf/current...

A Unified Strategy to ent-Kauranoid Natural Products: Total Syntheses of ��

(–)-Trichorabdal A and (–)-Longikaurin E

John T. S. Yeoman, Victor W. Mak, and Sarah E. Reisman. J. Am. Chem. Soc. 2013, 135, 11764.

Kara George Rosenker Wipf Group - Current Literature

24 August 2013

MeH

OHMe

O

O

O

OH(–)-trichorabdal A

MeH

Me

O

OAcOOH

OH

(–)-longikaurin E

MeH

TBSOMe

O O

Kara Rosenker @ Wipf Group of 15 8/24/2013

The ent-Kaurenes (Diterpenoids)

H

H

ent-kaurene

•  Isodon species have a long tradi1on in Chinese folk medicine for their cura1ve proper1es

•  Over 600 known Isodon diterpenoids (mainly ent-‐kaurenoids) •  Classified into 11 groups and 5 subgroups based on the

different oxygena1on and cleavage paEerns •  Many of these compounds exhibit potent an1bacterial, an1-‐

inflammatory, and an1cancer proper1es

Sun, H.-D.; Huang, S.-X.; Han, Q.-B. Nat. Prod. Rep. 2006, 23, 673. Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach. 3rd ed.; Wiley: Great Britain, 2008.

ent-kaurene

H

H

(–)-copalyl diphosphate

H

H

OPPOPP

geranylgeranyl diphosphate(GGDP)

CPS KS


H

H

ent-kaurene

The ent-Kaurenes (Diterpenoids)

MeH

MeO O

OAcHO

maoecrystal Z

OH

O

OMe

HO

MeMe O

O

maoecrystal V

Sun, H.-D.; Huang, S.-X.; Han, Q.-B. Nat. Prod. Rep. 2006, 23, 673.

MeH

OH O

O

O

OHtrichorabdal A (R = H)

trichorabdal B (R= OAc)

MeH

Me

O

OAcOOH

OH

longikaurin E

MeH

OHO O

O

O

OHR

shikodonin

•  Isodon species have a long tradi1on in Chinese folk medicine for their cura1ve proper1es

•  Over 600 known Isodon diterpenoids (mainly ent-‐kaurenoids) •  Classified into 11 groups and 5 subgroups based on the

different oxygena1on and cleavage paEerns •  Many of these compounds exhibit potent an1bacterial, an1-‐

inflammatory, and an1cancer proper1es


H

H

ent-kaurene

•  (–)-‐Longikaurin E was isolated in 1981 from Rabdosia longituba -  In vitro growth inhibi1on against 5 human cancer cells lines

(IC50s < 10 µM; HL-‐60, SMMC-‐7721, A-‐549, MCF-‐7, SW-‐480) •  (–)-‐Trichorabdal A was isolated in 1981 from Rabdosia

trichocarpa -  Potent in vivo an1tumor ac1vity, IC50 = 548 nM (HeLa cells) -  Modest an1bacterial ac1vity against H. pylori

The ent-Kaurenoids: (–)-Trichorabdal A and (–)-Longikaurin E

1

2

34

5

67

8

9

10

11

1213

14

15

16

17

18 19

20

MeH

OHMe

O

O

O


O

H

6,7-seco-ent-kaurene

OR7

20

6

8910

5

Fujita, E.; Fuji, K.; Sai, M.; Node, M.; Watson, W. H.; Zabel, V. J. Chem. Soc. Chem. Commun. 1981, 899.; Fuji, K.; Node, M.; Sai, M.; Fujita, Takeda, S.; Unemi, N. Chem. Pharm. Bull. 1989, 37, 1472.; Kadota, S.; Basnet, P.; Ishii, E.; Tamura, T.; Namba, T. Zbl. Bakt. 1997, 286, 63. Fujita, T.; Takeda, Y.; Shingu, T. Heterocycles 1981, 16, 227.Zhao, W.; Pu, J.-X.; Du, X.; Su, J.; Li, X.-N.; Yang, J.-H.; Xue, Y.-B.; Li, Y.; Xiao, W.-L.; Sun, H.-D. J. Nat. Prod. 2011, 74, 1213.

MeH

Me

O

OAcOOH

OH

(–)-longikaurin EH

H

OOHO

R

R

6

7

20

7,20-epoxy-ent-kaurane

510 8

9


Synthesis of 6,7-seco-ent-Karanoids

•  In 1986 Mander and co-workers reported a 33-step synthesis of 15-desoxyeffusin

Kenny, M. J.; Mander, L. N.; Sethi, S. P. Tetrahedron Letters 1986, 27, 3923. Kenny, M. J.; Mander, L. N.; Sethi, S. P. Tetrahedron Letters 1986, 27, 3927.

O OMe

EtO2CH O

MeO OMe

CO2H 11 steps

H

H O

OO

O

3 steps

O

H O

O

O

MOM MOM MOM8 steps

O

H

OO HH

H

OHO

OHAcO 15-desoxyeffusin

6,7-seco-ent-kaurene7,20-epoxy-ent-kaurane

6

7

20

AcO

MeH

OH O

OAcO15

15-desoxyeffusin

H5IO610 steps


Synthesis of 6,7-seco-ent-Karanoids

•  12 years later this group completed a 29-step semisynthesis of longirabdolactone

Adamson, G.; Mander, L. N. Aust. J. Chem. 2003, 56, 805.

OHH

CO2HHHO

O

OC

gibberellic acid(commercial)

OHH

OHH

CO

O

CHO

KH

H

H

OO

CO

OMe

H

OOO O86%

O

H

O

MeO2C

O HH

H

OHO

OO 6,7-seco-ent-kaurene

7,20-epoxy-ent-kauranes

6

7

20

76

MeH

OO O

O

O

longirabdolactone

MeH

OHO O O

3 steps 4 steps


Total Synthesis of (–)-Maoecrystal Z

MeH

OMe O O

H

O HH

MeH

MeO O

OHHO

SmI2, LiBrt-BuOH

THF, -78 °C

54%

MeH

OMe O O

H

OH

2 rings4 stereogenic centers

SmIII

(–)-maoecrystal Z

Cha, J. Y.; Yeoman, J. R. S.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964. Szostak, M.; Procter, D. J. Angew. Chem. Int. Ed. 2012, 51, 9238.

MeH

MeO O

OAcHO

(–)-maoecrystal Z

OH

– TiIII-mediated reductive epoxide coupling– SmII-mediated reductive cascade cyclization

•  First total synthesis of maoecrystal Z was reported in 2011 by Reisman and co-workers – 12 steps from (–)-γ-cyclogeraniol

OTBSMeMe

2 steps fromγ-cyclogeraniol

MeH

TBSOMe

O O

O Cp2TiCl2, Zn0

2,4,6-collidine⋅HClTHF, 23 °C

74%

CO2CH2CF3

MeH

TBSOMe

OCH2CF3

O

O TiIV

single diastereomer


A Unified Strategy to ent-Kauranoid Natural Products

MeH

OH O

O

O

OHtrichorabdal A (R = H)

trichorabdal B (R= OAc)

MeH

Me

O

OAcOOH

OH

longikaurin E

MeH

OHO O

O

O

OHR

shikodonin

MeH

MeO O

OAcHO

maoecrystal Z

OH

O

OMe

HO

MeMe O

O

maoecrystal V

OTBSMeMe

2 steps fromγ-cyclogeraniol

O MeH

TBSOMe

O O

Cha, J. Y.; Yeoman, J. R. S.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964. Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764.


Title Paper: Retrosynthetic Design for ��Trichorabdal A and Longikaurin E

Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764.

MeH

Me

O

OAcOOH

OH

(–)-longikaurin E

MeH

TBSOMe

O

O OR

MeH

OHMe

O

O

O


Sm-mediatedreductivecyclization

Pd-mediatedoxidativecyclization Me

H

TBSOMe O ORO

SiR'3

MeH

TBSOMe O O

H

O HMe

H

TBSOMe O O

TBSO

OHMeMe

Sm-mediatedreductivecyclization

intermediate in the synthesis of maoecrystal Z

(–)- γ-cyclogeraniol


Synthesis of Common Intermediate

OHMeMe

(–)- γ-cyclogeraniol

OTBSMeMe

O

3:1 anti:syn

1. TBSCl, imidazole CH2Cl2

2. m-CPBA, NaHCO3 CH2Cl2

91% (2 steps)

Cp2TiCl2, Zn0

2,4,6-collidine⋅HClTHF, 23 °C

CO2CH2CF3

MeH

TBSOMe

OCH2CF3

O

O TiIV

Cha, J. Y.; Yeoman, J. R. S.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964. Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764.

NMe

OTBS

OPh

Me

OHNMe

OPh

Me

OHHO

O PivCl, NEt3

THF; then (R,R)-pseudoephedrine

82%

I OTBS

LDA, LiClTHF

1. BH3⋅NH3 LDA, THF

2. I2, PPh3, im. CH2Cl2

85% (2 steps)92%

A

O

TBSO

OTBSO

MeMe

MeH

TBSOMe

O O74%

single diastereomer

TBSO

ILHMDS, 4:1 THF/HMPA

0 to 23 °C

63%intermediate in the synthesis

of maoecrystal Z

A


Synthesis of Oxidative Cyclization Substrate

MeH

TBSOMe O OMOMO

TBS

KHMDSTBSCl, DMPU

THF, -78 °C

85%


O

TBSO

OTBSO

MeMe

O

O

OTBSO

MeMe

1. n-Bu4NHSO4 p-TsOH MeOH, 0 °C

2. DMP, DCM77% (2 steps)

SmI2, LiBrt-BuOH

THF, -78 °C

57%

MeH

TBSOMe O O

O

H H

SmIII

MeH

TBSOMe O O

MOMO

H

HMOMCl

n-Bu4NI, DIPEA

DMF, 45 °C

91%

MeH

TBSOMe O O

HO

H

HMe

H

TBSOMe O O

H

O SmIII

single diastereomer


Reaction Optimization: �� Pd-Mediated Oxidative Cyclization

MeH

TBSOMe O OMOMO

TBS

MeH

TBSOMe

O

O OMOM

PdII

DMSO, 45 °Cair

•  Little difference observed when the reaction was conducted under an air or oxygen atmosphere

•  Entry 3 conducted in MeCN gives lower yield and increased side product formation

•  All other solvents tested gave only trace quantities of product (toluene, glyme, dioxane, t-BuOH, DMF)


entry Pd source addi/ve yield (%)

1 Pd(OAc)2 (0.1) – 7

2 Pd(OAc)2 (1.0) – 35

3 Pd(OAc)2 (1.0) – 28*

4 Pd(TFA)2 (1.0) – 19

5 PdCl2 (1.0) AgBF4 (2.0) 5

6 PdCl2 (1.0) – 0

7 Pd(OAc)2 (1.0) H2O (5.0) 38

8 Pd(OAc)2 (1.0) K2CO3 (5.0) 0

9 Pd(OAc)2 (1.0) AcOH (0.5) 56

10 Pd(OAc)2 (0.1) AcOH (0.5) 7

11 Pd(OAc)2 (1.0) AcOH (1.0) 31

12 Pd(OAc)2 (1.0) p-‐TsOH (0.5) 46

13 Pd(OAc)2 (1.0) BzOH (0.5) 32

14 Pd(OAc)2 (1.0) PivOH (0.5) 40

First example of a Pd-mediated oxidative cyclization of a silyl ketene

acetal to generate an all-carbon quaternary center


Total Synthesis of (–)-Trichorabdal A

MeH

TBSOMe

O

O OMOM

O3, DCM-94 °C;

then PPh3

69%

MeH

TBSOMe

O

O

O

OMOM

MeH

TBSOMe

O

O

O

OMOM

Me2NCH2NMe2Ac2O

DMF, 95 °C

82%

MeH

OHMe

O

O

O


1. 6 M aq. HCl dioxane, 45 °C

2. TEMPO, PhI(OAc)2 DCM

73% (2 steps)

15 steps from (–)-γ-cyclogeraniol



Total Synthesis of (–)-Longikaurin E

MeH

TBSOMe

O

O OMOM

6 M aq. HCl

dioxane, 45 °C

89%

MeH

HOMe

O

O OH

1. TEMPO PhI(OAc)2

2. Ac2O DMAP58% (2 steps)

MeH

OMe

O

O OAcH

MeH

MeOAcOOH

OH MeH

Me

O

OAcOOH

OH

(–)-longikaurin E

SmI2

THF, 23 °C

55%(75% BRSM)

1. O3, DCM, -94 °C; then PPh3

2. Me2NCH2NMe2 Ac2O, DMF, 95 °C

44% (2 steps)

17 steps from (–)-γ-cyclogeraniol



Conclusions and Outlook

•  A unified synthetic strategy has been applied to the first total syntheses of (–)-trichorabdal A and (–)-lonikaurin E –  15 and 17 steps, respectively from (–)-γ-cyclogeraniol

•  PdII-mediated oxidative cyclization reaction was employed to generate the an all-carbon quaternary center and build the bicyclo[3.2.1]octane core

•  Three architecturally distinct ent-kauranoids were prepared from a common spirolactone intermediate

MeH

OHMe

O

O

O


MeH

Me

O

OAcOOH

OH

(–)-longikaurin E

MeH

MeO O

OAcHO

(–)-maoecrystal Z

OH

O

TBSO

OTBSO

MeMe


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