JACS I Love ‘71Dan O’Malley

Baran Lab Group Meeting 9/10/2003

Corey Prostaglandins E8 and F3a

Corey et. Al. JACS 1971.1489-90, 1490-91, 1491-92.

Tl

Tl2SO4

KOHMOMCl OCH3

Cl

CN

O

H3COH2C

O

OR

CH2OCH2C6H5X

O

OH

CH2CO2H

CH2C6H5

1) AmphetamineResolution2) Iodolactonization

1)mCPBA

2)Base

1 23

4

5

6: X=I; R=H7: X=I; R=PB8: X=H; R=PB

PBClBu3SnH

PB=p-Phenylbenzoyl

Magically BecomesO

OTHP

R

O

9:R=CH2OH10: R=CHO

py2.CrO3

1)

2) KOH

Prostaglandins Part 2

O

HO

O

OH

OH

HOOH

OH

R

O

O

11 1213: R=Ch2OH14: R=CHOpy2•CrO3

Ph3P CHC2H5

O

O

Et

HCl

MeOHOH

X

Et

15 16: X=OH17: X=I18: X-PPh3

O

OTHP

CHO

O

10

18O

OTHP

O

Et

OR11: R=H12: R=THP

ab a: 1)TsCl, py 2)NaI

b: PPh3

DHP,TsOH

Prostaglandins Part 3.

O

OTHP

O

Et

OTHP12

DIBAL O

OTHP

OH

Et

OTHP

HO2C

(CH2)3 PPh3

13

RO

OH

CO2H

OR14: R=THP15: R=H Prostaglandin F3a

14

HO

CO2H

OH

O

1) CrO3 H2SO4

2) AcOH, H2O

Prostaglandin E8

AcOH, H2O

2 Syntheses of (+)-Camptothecin

N

NO

O

OOH

Camptothecin

Antitumor and antileukemia alkaloidfrom Camptotheca acuminata tree

Stork Camptothecin

N

OCO2Et

CO2Et NH2

CHO

NaOH N

N

R'

R

12:R=CO2Et; R'=CO2H3:R=H; R'=CO2Et4:R=COCH2CO2Et R'=CO2Et

N

NO

X

R5: R=CO2Et; X=O6: R=H; X=O7: R=H; X=H, OH

NaOEt

N

NO

Ac2O

8

O

OEt

Li OCO2Et

N

NO

O

X

CO2R

9: X=O; R=Et10: X=O; R=H11: X=H,OH; R=H12: X=H,OAc;R=H

DDQ N

NO

O

OAc

CO2H

13

ab

cd

efg

a:1)50% HIO4 2) EtOH, HClb:

c: !0%AcOH, reflux d:NaBH4-

e: HCl reflux f: NaBH4, EtOH g:Ac2O, py

ClOC CHO2Et

Stork Camptothecin part 2

N

NO

O

OAc

CO2H

N

NO

O

OOH

Camptothecin

1) NaOH, H2O

2)NaBH43) HCl

Stork and Schultz. JACS 1971 4074-4075

Danishefsky (+)-Camptothecin

Danishefsky et. Al. JACS, 5577-78. (1971)

H2N

O

H

MeO2C CO2Me EtO

HOEt

NH

MeO2C

CO2Me

HCl, H2OAcetone N

CO2Me

MeO2C

CO2R'

O12 3: R=CHO; R'=Et

4: R=CO2H; R'=Et5: R=CO2Me; R'=Me

R

N

CO2Me

CO2H

O

HO

MeO2C

4% HClreflux

N

CO2Me

CO2H

O

O

NaOH

o-Aminobenzaldehyde

N

N

O

COR''

R'

6 7

8: R=H9: R=Et

CrO3 H2SO4

HCl MeOH

NaH.DMEEtI

ParaformaldehydeH2SO4

N

N

O

NaOMe

MeOH

R

8:R=CO2H; R'=R"=H9:R=CO2H; R'=H; R"=Me 10: R=R'=H; R"=Me11: R=H; R'=Et; R"=Me

ab

c

a: esterification b:CuO, heat c: NaH.DME, EtI

O

R

O

12: R=H13: R=OHH2O2, KOtBu

C

CO2Et

EtO2C

Cis-ZeatinO

N1)EtOh, Ph, Hydroquinone, -30o C2)KOH O

NH

Zn AcOH

OH H2N

N

N NH

N

Cl

+ n-BuOHreflux

N

N NH

N

NHHOH2C

cis-Zeatin

Leonard et al. . JACS 1971. 3057-58

(+)-SeychelleneO

O

OR

O

1: Wieland-Miescher Ketone2: R=H3: R=THP

NaBH41)LiCuMe2

2)AcCl

OTHP

AcO4

OTHP

AcOO

OTHP

X

OAc56: X=O7: X=CH2

OR'

OR

mCPBA Heat (PPh3)3RhClH2

8: R=Ac; R'=THP9: R=H; R'=THP

O

OTHP

O

OTHP

10: Favored

11: Disfavored

Base

a

a: "The Usual Method"

CH2PPh3

KOH

CrO3, py

Seychelline Part 2

O

OTHP OTHP

HO

OTHP

OR'

RO

10 11 12

13: R=H; R'=THP14: R=Ts; R'=THP15: R=Ts; R'=H

RO

O

O

HO

16 17

18 Seychelline

MeLi SoCl2py

1)BH3

2) NaOH, H2O2

CrO3 ,py NaHDMSO

MeLi, Et2OReflux

SOCl2py

ab

Stork (+)-Lupeol

H

H

H

H

HO

Lupeol

Pentacyclic Triterpene10 Asymmetric Centers

Stork et. Al. JACS 1971. 4945-47.

Lupeol 1

O

H

H

OBz

O

H

H

OBz

1)Allyl OrthoformateAllyl Alcohol, TsOH

2)py reflux

Et2AlCN

O

H

H

OBz

CN

H

H

OBz

R

O

O

1)Ketalization2) LAH, THF reflux

3)AcOH, THF, MeOH4) Re-benzoylation

12

3 4: R=CHO5: R=CH2OH

NaBH4

Lupeol 2

H

H

OBz

CH2OH

O

O

5

H

H

OH

1) Mesylation2)3%HCl, THF

3) Saponification

O

H

H

OH

O

1)Glyme, tBuOH, Li, NH32)HMPA3)MeI

H

H

OBz

HO2C

O

1)Benzoylation2)Disiamylborane3)CrO3, H2O4

1)Enol Lactonization2)EtMgBr3)NaOMe

H

H

OBz

O

6

7

89

Lupeol 3

H

H

OBz

O

9

Base, Allyl Bromide

H

H

OBz

O

H

H

OH

O

H

H

10

11

1)Dioxolane Formation2)9-BBN3)CrO3, H2SO44)Enol Lactonization5)EtMgBr6)NaOMe

H

H

OH

O

H

1)Li, NH3

2)MeI

H1112

Lupeol 4

H

H

OH

O

H

12

1)Ketalization2) [O]

3)NaHMDS4)Ac2O

H

H

OAc

HO

O13

1)O32)NaBH4, NaOH

3)CH2N24) Tosylation

H

H

HO

O

MeO2C OTs

14

H

H

HO

O

MeO2C

15

NaHMDS

HH

HH

Lupeol 5

H

H

H

H

O

O

MeO2C

15

H

H

H

H

HO

Lupeol

1) MeLi, Dioxane reflux2)POCl3, py3)deketalization4)NaBH4

(+)-Gibberelin A15

O

H

H

O OH

O

Gibberelin A15

Nagata et. Al. JACS 1971 5740-58.

Gibberelin 1

MsN

O

H

H

Isoprenyl AcetateTsOH reflux MsN

OAc

H

H MsN

OH

H

H

NaBH4

MsN

H

OHO

CHO

MsN

OH

OR

H

H

X

1 23

45:X=O; R=H6:X=O; R=Ac7:X=CH2; R=H

1)O32)Zn AcOH3)NaHSO3

NaOH

aba:"usual manner" b:CH2PPh3

CrO3 H2SO4

MsN

OH

H

H

O MsN

H

H

OSOCl2, py

8 9

Gibberelin 2

MsN

H

H

O

9

MsN

H

H

O

CN

10

Et2AlCN

MsN

H

H

OH

CN

Al(OiPr)3

PhMe

11: dr 5:1

MsN

H

H

OR

CHO

1)DIBAL2)AcOH, NaOAc

12: R=H13 :R=THPDHP

P

O

OEtOEt

N

1)

2)Oxalic Acid3)10% HClO4

MsN

H

H

OR

CHO14: R=H15: R=TsTsCL, py

Ac2O ZnCl2 MsN

H

H

X

OTs

CH(OAc)216: X=CH217: X=O

O3Zn AcOH

Gibberelin 3

MsN

H

H

O

OTs

CH(OAc)217

KOH MsN

H

H

OTs

O

H3CO

CHO

MsN

H

HO

HO

CHO

1) pyrrolidineN-methylpyrrolidine2)50% AcOH

MeOH

py2•CrO3MsN

H

HO CHO

O

K2CO3H2O

18

19 20

MsN

H

H

O OH

CHO

H2NNH2

KOHMsN

H

H

O OH2122

Gibberelin 4

MsN

H

H

O OH22

NH

H

H

O OH23

Li NH3TFAA, py

NR

H

H

O OR'

24: R=CF3CO; R'=H25: R=CF3CO; R'=Me26: R=H; R'=Me

ab

a: CH2N2b:K2CO3

Pb(OAc)4K2CO3

N

H

H

O OMe

27: Mixture of Regioisomers

py2•CrO3O

H

H

O OMe

(H)HO

(HO)H

28

O

H

H

O OMe

O

29: Regioisomers Seperated

NaNO2 AcOH

H2O NaOAc

Gibberelin 5

O

H

H

O OMe

O

29

O

H

H

O OH

O

g-CollidineLiI, PPH3

Gibberelin A15

Heathcock (+)-a-Bulnesene and(+)-Bulnesol

H

a-Bulsenene

H

OHBulnesol

Heathcock et. Al. JACS 1971 1746-56

Bulnesene 1OBn

O

O

1: From Wieland-Miescher Ketone

OBn

O

O

OHH

BH31)2) NaOH, HOOH

2: 2:1 dr

OBn

O

O

OH

py2•CrO3

3: 2:1 dr

OBn

H

1) CH2PPh3

4: Single Diastereomer

O

2) AcOH, H2ORh/Al2O3

H2

OBn

HO

5: Diastereomers Seperated

PPh3

OBn

H

H(CH3)

CH3(H)6

OBn

H

OH

1) BH3

2) NaOH, HOOH

OBn

H

O

1)py2•CrO32)HCl

7 8: Single Diastereomer

OH

H

O

H2 Pd-C

9

Bulnesene 2OH

H

O

9

OR

H

CH2PPh3

10: R=H11: R=Ts

H

a-Bulsenene

OBn

H

O

8

MeLi

OBn

H

OH

12

1)Pd-C, H2

2)TsCl, Py

OTs

H

OH

H

OHBulnesol

AcOH

13

AcOH

MethodologiesNO2

+

O

NO2

O

TiCl3

O

O

O

cis-jasmoneMcMurry and Melton, JACS 1971, 5310-11.

HNiPr2

85% crude

ClO H3CS SCH3

OR

NaSCH3

1 2: R=H3:R=MeNaH, MeI

H3CS SCH3

Li+

4

CHOsynthon

4 +

O

OH

SCH3

SCH3

OH

O

AgNO3

Corey et. Al. JACS 1971 1724-1729