Brian RaymerEvans Group Seminar

October 22, 1999

Lead References:

Corey, Guzman-Perez, ACIEE, 1998, 37, 388 - 401Fuji, Chem. Rev., 1993, 93, 2037-2066

Asymmetric Quaternary Center Construction

Quaternary Center: Carbon with four carbon substituents

• Enolates and Enamines• Cycloadditions• Sigmatropic Rearrangements• Cyclopropanation• Palladium Mediated Construction• Lewis Acid Catalyzed Rearrangements• Radical Cyclizations

Definition:

Contents:

Asymmetric Quaternary Center Construction

O

Me Me

Me

Natural Products from Camphor

Money, Nat. Prod. Rep., 1985, 2, 253

Ph CO2H

O

NO

Ph

O

NH2H

OH

NO

Ph

OR1

R2

∆Ph CO2H

O R1R2

O O

R1R2

R1 R2

RHO

O

R2

R1O

HN HN

R1R2

R2R1

Meyers Bicyclic Lactams

+85%

1. LDA, R1X2. LDA, R2X

50 - 90%

10% H2SO4butanol

• R's may be non-branched alkyl, allyl or benzyl

Review: Meyers, Brengel, CC, 1997, 1

Meyers et al, JACS, 1984, 106, 1146

> 95% ee

70-90%

valine dx.

ClCl

MeO

O

n-Pr

ClCl

MeO

O

n-Pr

ClCl

MeO

O

n-PrMe

O

Cl

Me

N

N

CF3

HH

OHH

Br

O

CO2MeO

O

CO2Me

OOO

O

O

OO

Me

Me

KOt-Bu

Enolate Alkylation and Michael Additions

Karady et al, JOC, 1986, 51, 4710

Bhattacharya et al, ACIEE, 1986, 25, 476

ClCH2CH=CClCH350% NaOH(aq)/Toluene

20 °C, high aggitation

H2C=CHCOCH350% NaOH(aq)/Toluene

20 °C, high aggitation

Merck Phase Transfer Catalyst

+

toluene, -78 °C76% yield, 99% ee

Cram Binol Derived Catalyst

Cram et al, CC, 1981, 625

99% yield, 92% ee

95% yield, 80% ee

O

O

MeMe

O NH

CO2H O

O

O

O

OH

Me MeH2SO4

N

OMe

O-OOC N

COO-

H

Desymmeterization: Amino-acid catalyzed Robinson Annulation

For additional examples: W. Trotter Seminar, April 1997

DMF, 16 °C

3 mol%

DMF, 95 °C

recrystallize

Hajos, Parrish, Org. Synth., VII, 363Hajos, Parrish, JOC, 1974, 1615

Wieland-Miescher ketone:Buchschacher, Furst, Gutzwiller, Org. Synth., VII, 368

~ 92% ee 99% ee76% yield

See also: Corey, Virgil, JACS, 1990, 112, 6431

• Dilution studies suggest three-center hydrogen bond.

• Nonlinear relatinship between enantiomeric purity of (S)-proline and product observed.

Puchot et al, CC, 1985, 441.Kagan et al, JACS, 1986, 108, 2353

O

O Me

O

O MeMe

MeMe

O

MeMe

O CO2MeO

MeO OMe

O

MeO OMe

H

CO2Me

MeMe

O

MeO OMeCO2Me

MeMe

O

O

MeO OMe

H

CO2Me

MeMe

OO

R

O

CO2Me

NaOMe, MeOH

Me

Me

Me

Me

Me

Me

Me

Me

MeMe

Me

Me

I

I

Tanabalin: Intermolecular Alkylation-Intramolecular Robinson Annulation

Watanabe, et al, TL, 1999, 40, 2545

1. LDA, MeI,THF-HMPA

69% yield, 6 steps

+82%

82 % yield,single isomer

Double Alkylation to set up...

...an alkylation and then a Robinson Annelation.

79% yield, 2 stepssingle isomer

2. LDA, prenyl bromide, THF-HMPA

L

NMg

O

t-Bu H Ot-Bu

R1Br

NMg

O

t-Bu H Ot-Bu

BrR1H

RH

R2CHO

N

OMe

OH

CO2t-Bu

N

OMe

O

Ot-BuO

OCOOMe

MeO

COOMeMe

S

Li

N O

t-Bu H Ot-Bu

Asymmetric Grignard Addition and Asymmetric Enamine Alkylation

Koga et al, Tet, 1981, 37, 3951

R1MgBr 1. R2X, HMPA2. H3O+

R1 = Ph, vinylR2X = MeI, BnI, allylBr, EtI, MOMCl

55 - 67% yield91 - 93% ee

Koga et al, JACS, 1984, 106, 2718

+

Ligand: 1.0 eq. HMPA

2.0 eq. THF

57% yield, >99:1 (R)

63% yield, 96:4 (S)

R

LDA, Toluene 1. MeI, Ligand

• strongly ligating HMPA suppresses underside attack• weakly ligating THF replaced by alkyl halide before alkylation

2. hydrolysis

O

N

OMe

RNO2

O

OR'

O

ONO2

R

R'Zn+

N

OMe

NO2

N

OMe

NO2

OOM

R

N Zn

O

N

ZnO

O

O2N

H

O2N

R

MeO

OMe

R

H

O

ONO2

R

R'

O

ONO2

R

R'

Chiral Leaving Groups: Nitroolefination

Fuji et al, JACS, 1989, 111, 7923

R=H, Me, Et,3.0 eq.R'=Me, Et, allyl

74 - 96% ee54 - 86% yield

re

re

si

re S-isomer

R-isomer

+-78 °C to - 50 °C0.3 to 2 hours

Cl

O

Me MeH

CNO

MeMeH

CN

OTBSNC

Cl

HMeMe

NC O

HCl

NC OH

H

CNOH

H

NaBH4 LiNEt2

CN-O

Cl

CNO

n-Bu4NF

O

MeMeH

CN O

Me MeH

CNOTBSNC

Cl

HMeMe

n-Bu4NF

cis- and trans-Decalins: β-Siloxy Unsaturated Nitriles

Fleming et al, Org. Lett., 1999, ASAP

py-MeOH

68%

(84% β-CN)(81% α-CN)

TPAP(100%)

90%

cis trans

see also: Stork, Boeckman, JACS, 1973, 95, 2016Effects of counterion on on nitrile anion orientation.

cis trans

1. NaBH42. LiNEt23. TPAP

57%90%

3:2 β:α • stereoselectivity not reported

• stereoselectivity not reported

Fe

CHO

Me

CHOMe

OO

O

CF3

CF3BN

N

O

N

O

Cu

CMe3Me3CN B

OMe

HO

H n-BuTs

OPP

O

F5

F5F5

F5

BF4

Catalytic Enantioselective Diels-Alder

CH2Cl2, catalyst+

99% yield, 90 % ee, exo:endo=88:12

100% conv., 92% ee, exo:endo=97:3

91 % yield, 98% ee, exo:endo=97:3

96% yield, 99%ee, exo:endo >90%?

-78 °C, 1.5 h -20 °C, 22 h-40 °C, 8 h -94 °C, 2 h10 mol % cat.5 mol % cat. 5 mol % cat.5 mol %cat.

5.0 eq. diene1.2 eq. diene 1.1 eq. diene4.0 eq. dieneCoreyEvans KundigYamamoto

2 SbF6-

ACIEE, 1994, 33, 1856JACS, 1991, 113, 8966ACIEE, 1995, 34, 798JACS, 1996, 118, 3049

2+

N

TBSO

PhPh

HN

MeOPhPh

OMe

CHO

Me

TBSO

N PhPh

Me CHO

Me

O

MeO

Me

Diels-Alder in Synthesis of Elemene

83 - 90%,2 steps

1.3 eq. dienophiletoluene, -10 °C

71% yield, 88% de

(-)-α-Elemene

Rawal, Kozmin, JACS, 1999, 121, 9562

++

Elemene: Chiral Amino Siloxy Diene Diels-Alder

1. Ph3PCH3Br n-BuLi, THF

2. aq. HCl, THF

81% yield, 2 steps

1. i-PrLi, CeCl3 Et2O, -78 °C

2. PCC, CH2Cl274% yield, 2 steps

1. i-PrLi, CeCl3 Et2O, -78 °C

2. HClO4, AcOH81% yield, 2 steps

O

AllocHN

Me

Me

CO2t-Bu

BCDO

AllocHN

Me

Me

CO2t-Bu

BCDO

AllocHN

Me

Me

CO2t-Bu

BCDH

O

O

O

TESOMe

O

Me

MeNHAlloc

O

O

MeOTBS

CO2t-BuOMs

O

O

O

TESOMe

O

O

MeOTBS

O

AllocHN

Me

Me

CO2t-Bu

B B

CC

D DF F

CO2t-Bu

32

1

35

6

G

32

1

35

6

G

32

1

35

6

G

A, desired exo product B, undesired exo product C, endo product

33 % 33 % 33 %

43 % 39 % 17 %

Reaction Conditions

toluene, 100 °C

dodecane, 70 °C

1. DABCO, TEA, benzene

2. 0.2 mM diene in dodecane, 70 °C, 78 %

6

32

35

11

3532

6

E E

G

Pinnatoxin Diels-Alder

Dimerization of dieneif Diels-Alder run athigh concentration

Kishi et al, JACS, 1998, 120, 7647

35

32

EF EF EF

•

HO

Li O

H

OEtMe

Me Me

O

EtO

OTBS

OBnO

OBn BnO

OTBS

BnOEtO

O

MeOTBS

OBnOH

OBn

O

MeN

OBnO

OBn

OH

H

H

OO

MeN

OBnO

OBnMe Me

O

H

OO

Bn

Me

NO

O

Bn

O O

NHO

OBn

OBnMe Me

H

3 4

Taxane CD ring system: 1,2-Addition and [3+2] Cycloaddition

Takahashi et al, JOC, 1998, 63, 5742

3.0 eq. 1, LDA, THF, -78 °C,

then 2, 10 min

1 2

70% yield+

dr=76:9:8:7no γ-adduct

46% yield,5 steps

+

56% yield 33% yield

NaOCl (aq.),0 °C, 15 min,

then Et3N,RT, 3 hours

elaborated toTaxane CDring system

see also: D. Halstead SeminarNitrile Oxide Cycloadditions

OCO2EtO

CMe3Et3SiO

OCO2Et

CMe3Et3SiO

O

OMeO

CMe3

CO2H

OMeO

CMe3

O

O

CMe3

HO

Ginkgolide B Syntheses: 2+2 Cycloadditions

hv, 366 nmhexanes

100% yield, 98:2 ds

Crimmins et al, JACS, 1999, ASAP

Ginkgolide B

1. (COCl)2, benzene

80%, 2 steps

[2+2]

Corey et al, JACS, 1998, 110, 649

Ginkgolide B

Ketene [2+2]:

Enone-Furan [2+2]:

2. n-Bu3N, toluene, ∆

Me Me

Me Me

MeMe

H

Me HMe

MeMe

Me HMe

Me

Me Me

Me

Me

Me

MeMe

Li, MeNH2

SiMe3

O OBn

MeMe

TDSO

MeMe

TDSO

O

MeMe

TDSO

O

OBn

F3B Me

Me

MeMe

SiMe3

Silphinene: Arene-Olefin meta-Cycloaddition and Nazarov Cyclization

Franck-Neumannet al, Tet, 1997, 53, 2103

Wender et al, TL, 1985, 26, 2625

+

hv

70%

Hg Lamp

74%

9:1 ds1:1 mixture Silphinene

Arene-Olefin meta-Cycloaddition

see also: Polyquinane Synthesis SeminarG. Peterson, Feb. 5, 1999

BF3 • OEt2ethylbenzene

∆

50%

Silphinene

Nazarov Cyclization

TDS = Thexyldimethylsilyl

Me3Si ORO

O

Me3Si

O

Me O

Me3Si

OSiMe2tBu

OH

Me

CHO

Me

Ireland-Claisen and Anionic Oxy-Cope

LDA, TBSI,THF, -78 °C then ∆

R = H

R = iPr

EDCI, iPrOH, DMAP57% yield, 2 steps

Aspidophytine: Ireland-Claisen

(+)-Dihydromayurone: Anionic Oxy-Cope

KH, [18]-crown-6, DME

DME, reflux, 3 hours75% yield,

95% "stereochemical fidelity"

Lee, Shin, Kim, JACS, 1990, 112, 260

Corey et al, JACS, 1999, 121, 6771

97% eeno "stereochemical fidelity" reported

no ee reported

N

NH2

MeOOMe Me

OHC

CHO

Oi-Pr

O

SiMe3

NMeOOMe Me

N

Oi-Pr

O

SiMe3NMeO

OMe Me

N

Oi-Pr

O

SiMe3

N

N H

Oi-Pr

O

MeOMeMeO

N

N H

Oi-Pr

O

MeOMeMeO

N

N H

Oi-Pr

O

MeOMeMeO

N

N H

Oi-Pr

O

MeOMeMeO

A B

A B

H+NCBH3-

Enamine Alkylation: Aspidophytine

Corey et al, JACS, 1999, 121, 6771

+

CH3CN, 23 °C,then TFAA, 0 °C,then NaBH3CN

B Quaternary Centerset by Ireland-Claisen

66% yieldselectivity not reported

+

O N

Me

ON Et

Me

ON

O

ON

O

MeMe

Et Me

ClMe

O

ClMe

O

NR2

OLAR

R1

NR2

OR

R1

LA

NR2

OR

R1

C OR

LAR1

NR2

C OR

Cl

O

R

Me

Lewis-Acid Catalyzed Claisen Rearrangement

MacMillan, Yoon, Dong, JACS, 1999, 121, 9726

75% yield, dr=95:5

72% yield, dr=99:1

10 mol% TiCl4 • THF2i-Pr2EtN, CH2Cl2, 23 °C

10 mol% TiCl4 • THF2i-Pr2EtN, CH2Cl2, 23 °C

NR3

NR3HCl

LA exchange

enantioselective version under development

Me

Me

Me

O

OH

CH3

H

Me

Me

MeO

O

O

Me

MeMe

O

OH

Me

Me

O

Me

H

NBN SO2

SO2

CF3

F3C

F3C

CF3

Br

Ph Ph

NB

N SO2

SO2

CF3

F3C

F3C

CF3

Br

Ph Ph

Stoichiometric Enantioselective Claisen Rearrangement

Corey et al, JACS, 1996, 118, 1229

1.0 eq. ligand2.0 eq. BBr3Et3N, toluene

85 % yield, 3:1 dr>99% ee

1.0 eq. ligand and BBr3i-Pr5-guanidine, CH2Cl2

86 % yield, 98:2 dr>98% ee

Corey et al, JACS, 1995, 117, 193

i-Pr5-guanidine: Barton's Base• strong, hindered base gives best results

O

Ar

NTs

Ar

NTs

CHOH O

H

HNTs

Ar

H

OH

H

N

O

H

Ar

LA

ArN

H

OLA

TsTs

ArN

H

OLA

Ts

NTs

OArAr

NTs

CHOH

NTsAr

NAr

OHTs

OHH

SnCl4, CH2Cl2

Intramolecular Ene and a Lewis-Acid Catalyzed Rearrangement

Mori et al, JOC, 1998, 63, 7586

230 - 240°C

66 - 72% conv.51 - 59% yield

10 mol% SnCl4

100 mol% SnCl4

89% 0% 0%

13% 6% 29%

+ +

Yield (%)

sole product

toluene, 4A MS

0 °C, 3 hours

Ph

N2

OMe

O

R

PhOMe

O

R

NHO2C S

OO

t-BuRh2

O

ON2

O

H

H

Me

O

N

O

H CO2Me

Rh2

1 mol % cat., CH2Cl2

Intermolecular and Intramolecular Cyclopropanations

Poulter et al, JOC, 1995, 60, 941

Davies et al, TL, 1993, 34, 7243

4

+pentane

58 - 91% yield> 83% ee

poor de

4

96% yield, ≥ 94% ee

α - cyclopropyl esters:

Presqualene diphosphate intermediate:

Bn

Bn

O

Bn

H

O

Bn

H

O

O

EtO2C

EtO2C

N

O

N

O

Me Me

CMe3Me3CCu(I)OTf

CH2Cl2N2CHCO2Et

CH2Cl2N2CHCO2Et

OH OEtO2CCH2Cl2

N2CHCO2Et OOO

Me

MeMe

H

Cu (I)-Catalyzed Cyclopropanation of Cyclic Enol Ethers

Andersson et al, JOC, 1998, 63, 6007

77% yield major diastereomerexo:endo=79:21, 96% ee

67% yield major diastereomerexo:endo=95:5, 96% ee

2 mol% active catalyst

2 mol% active catalyst

52% yield major diastereomerexo:endo=91:9, >95% ee

2 mol% active catalyst 10% H2SO4dioxane, ∆15 hours

(+)-Quebrachamine

37% overall yield

Quebrachamine:

Rh2Me O

CO2MeN2 CO2Me

MeO

HCl • HN

Me

NO

O

t-Bu

O2CH

O

COCHN2

H

OMOM

MeOH

OH

OMOM

MeO

O

CH2Cl2O

H

OMOM

MeOH

OH

OMOM

MeOH

O

Rh Catalyzed C-H insertion

CH2Cl2, -20 °C

White, Hrnciar, Stappenbeck, JOC, 1997, 62, 5250

Hashimoto et al, Synlett, 1996, 85-86

4

84% yield90% ee

FR115427:

Morphine:

(S)-FR115427

Rh2(OAc)4+ +

50% ~ 15% ~ 15%

(+) - Morphine

BnN

BnN

TBSO OTBS

OO

I I

BnN

BnN

OO

I I

OO

NBnBnN

NBn

BnN

O O

OTBSTBSO

O

O

OO

NH

N

HNN

H

HMe

Me

NH

N

HNN

H

HMe

Me

N

N

N

N

Me

H

Me

H

10% (PhP3)2PdCl2

Et3N, DMAC

10% (PhP3)2PdCl2

Et3N, DMAC

AcOH, ∆

Vicinal Stereogenic Quaternary Carbon Centers

Overman et al, JACS, 1999, 121, 7702

(-)-chimonanthine

meso-chimonanthine

(+)-calycanthine

100 °C, 90%

100 °C, 71%

steps

steps

60%• TBS substituents prefer a bis-axial orientation• acetonide prefers a bis-equitorial orientation

"Stereoselection....extremely high."

BnN NBn

OOH H O O

OTfTfO

OO

BnN NBn

OO

BnN NBn

OOOTf

NaRO OR

NH

N

HNN

H

HMe

Me

Chimonanthine Revisited: Dialkylation

meso-chimonanthine

2.1 eq. NaHMDS,THF, -78 °C, 92%

• Na+ scavenger reduces selectivity

single isomer

Overman, et al, ACIEE, 1999, accepted

BnN NBn

OOH H O O

OTfTfO

NR

O

RNO

NBnBnN

O

O OOLi

O O

OTf

NH

N

HNN

H

H

Me

Me

Chimonanthine Revisited: Dialkylation

Overman, et al, ACIEE, 1999, accepted

2.1 eq. LiHMDS,THF/DMPU, -78 °C, 55%

(+)-chimonanthine

• trace amounts of other C2 isomer• 20% cis-spirooxindole formed

MOMO

TfO

OO

Me

H

OSPDBT

Me

MOMO OO

Me

HTBDPSO Me

MOMO OO

Me

HTBDPSO Me

Kinetic Resolution by Asymmetric Heck Reaction

Shibasaki et al, TL, 1999, 49, 311

racemic

ligand(mol %)

reactiontime (h)

Yield % β:α % ee of β

(R,R)-CHIRAPHOS (40)

(R)-BINAP (40)

(R)-Tol-BINAP (40)

20

2

1.5

14

17

20

4

97

96

6:1

5:1

11:1

β α

Pd(OAc)2 (20 mol %)Ligand

K2CO3 (2.5 eq.)Toluene, 100 °C

+

Fe

Me

OO

Me

OO

NMePPh2

PPh2

MeHCH2CH2OH

OAc NaH, THF

Ph2PPh2P

O

ON

H

COOMe

Me

OO

Me

OO

OAc NaH, THF

PdP

P

R

NuPdP

PPd

P

P

R

Nu

O

Palladium Catalyzed Allylation

Hayashi et al, JOC, 1988, 53, 113

88% yield, 81% ee

+

[(η3-C3H5)PdCl]2, ligand

52% yield,52% ee(89% conversion)

+

*

*

Hayashi et al, CC, 1982, 1162

[(η3-C3H5)PdCl]2, ligand

*

COOMeMe

RTBSOTBSOR

I

Me

MeOH, H2O 4.0 eq. NEt3

DMF, O2 TBSOR

CO2Me

Me

Me

RTBSOH

COOMeMe

TBSO H

COOMeMe

O

Me

Me OO

H

Type II Carbopalladation

Negishi et al, Org. Lett., 1999, 1, 165

CO (1 atm)5% PdCl2(PPh3)2

R = H 91% yield, 94% deR = n-Bu 84% yield, 95% de

R = -(CH2)2CH=CH2 65% yield, 85% de

R = -(CH2)2CH=CMe2 80% yield, 93% de

O2, 85 °C

less than 2%observed

less than 5%observed

+ +

1. TBAF2. (COCl)2 DMSO

87% yield

1. MeMgCl2. NaOH3. H2SO4

Colvin-Raphael lactone

Precursor for trichoderminand trichodiene

no yieldindicated

Colvin-Raphael lactone:

Carbopalladation - Carbonylative Esterification:

Me

OHMe Me

Me

OBnMe Me

OBn

OMe Me

MeSnCl4O

OTES

CH(OMe)2

O

OMeH

O

OHMe

Br Oexcess KH

Me

O

1,2 Rearrangements

Abad et al, JOC, 1999, 64, 1741

1. Sharpless AE89% yield, 98% ee

2. NaH, BnBr, 88% yield 85%

no loss of ee

Herbertene and Herbertenol:

SnCl4 (1.1 eq)

CH2Cl2, -78 °C to 23 °C57%

Magellanine:

Overman et al, JACS, 1993, 115, 2992

THF, -78 °C to 25 °C72 % yield

Cyclobutene adduct:

Harmata et al, Synthesis, 1999, 1534

MeMe

Me

Br

MeMe

Me

S S

NMe

NHTs

Me

SMe

S MeMe

S

CR

N

SR'

TsN

Me

R'R

-S

N S Me

TsN

NaH NaH

SO

ONHHN

SMe

SMe

Bakkenolide: 2,3 Rearrangement

Evans, et al, JACS, 1977, 99, 5453

allylic carbazate highly stereoselective

62% yield75% crude yield

OBnHO

OMe

H

OMe

O OBn

OHO

Me

TMSMe

O

OH

TMS

Me

H

OHHO

Me

H

OHHO

H H

Cationic Cyclizations

Corey et al, JACS, 1997, 119, 9929

TiCl4CH2Cl2

86%

Vitamin D metabolite precursor:

Neotripterifordin:

1.5 eq. SnCl4, CH2Cl2

-95 °C, 72% yield

5:1 ratio of isomers

+

Takano et al, CC, 1989, 1893

NH

NN

BnOO

O

H

H

N NN

BnOO

O

H

HBr

NH

NN

BnOO

O

H

HBr

OHNN

O

O

H

H

HN

OBnO

NBS, AcOHTHF, H2O

Spirotryprostatin A

Danishefsky et al, JACS, 1999, 121, 2147

+

• Other conditions: OsO4, pyr, THF, then NaHSO3 (19%) ort-BuOCl, THF, then H2O, MeOH (42%)

90% yield

undesired stereoisomer

• TBS protected hydroxyl gives same stereochemistry

NH

NBocOMe

OH

NH

NBocOMe

OHBr

OH

NBS, AcOHTHF, H2O

R R

NBoc

CO2MeHN O

R

TFA, CH2Cl2

NH

CO2MeHN O

R

HN O

R

NN

O

O

H

H

TrocNCl

OH

Spirotryprostatin A

Danishefsky et al, JACS, 1999, 121, 2147

desired stereoisomer

R=OBn

R=C(Me)2SPh 70%

1. Et3N, CH2Cl2, 1, 0 °C to RT

2. Zn, THF, MeOH, NH4Cl (aq)68% yield, 2 steps

1

stepsSpirotryprostatin A

R=OBnR=C(Me)2SPh

63% yield

61% yield

N

N

SO

Ph

CO2Me

PhSN

NCO2Me

N

NH CO2Me

TFA, TFAA

N

CO2MeO

O

SEtO

OMeMeO

NO

O

MeO

MeO

CO2Me

O

SEt

RN

R'

O

O

SEt

RN

R'

O

O

RN

R'

O

SEt

RN

R'

O

O

SEt

RN

R'

O

O

O

Pummerer Rearrangement

Bonjoch et al, JOC, 1996, 61, 7107

1. Raney Ni2. hv

toluene80 °C, 2 hours63% yield

32% yield,2 steps

1. Ac2O, TsOH2. TsOH

Toluene, 70%

Padwa et al, JOC, 1996, 61, 4888

Deethylibophyllidine

Erythrinane Skeleton

+

++-

Me

H

MeCO2R*

MeO

Me

H

Me

MeO

H

Me

MeMeOO

OO

O

MeO

MeMe

Ph

MeO

MeMe

Ph

OMe

Me

Me CO2R*

OMe

Me

R*O2C MeO

Mn(III) Mediated Radical Cyclization

Snider et al, JOC, 1993, 58, 7640

R* = (+)-8-phenyl-menthol ester

(-)-O-methylpodocarpinolprecursor

1. Mn(OAc)3 • 2 H2O MeOH, 0 °C, 50%

2. Zn, HCl, ether, 65%

disfavoredfavored

see also: V. Cee Seminar on Mn(III) radicals, April 27, 1999

• 82% de after cyclization• 50% major and 6% minor diastereomer isolated

Lanthanide Triflate Catalysis: Yang et al, JACS, 1999, 121, 5579