Off To a Great Start:

First Syntheses by Three Untenured Synthetic Organic Chemists

Andrew J. PhillipsAssistant Professor (2002)

University of Colorado BoulderPostdoctoral Research: Peter Wipf (Pittsburgh)PhD: University of Cantebery (New Zealand)

Joseph M. ReadyAssistant Professor (2003)

University of Texas Southwestern Medical CenterPostdoctoral Research: John L. Wood (Yale)

PhD: Eric N. Jacobsen (Harvard)

Mohammad MovassaghiAssistant Professor (2003)

MITPostdoctoral Research: Eric N. Jacobsen (Harvard)

PhD: Andrew Meyers (Harvard)

Enantioselective Total Synthesis of (+) and (-)-Nigellamine A2J. Am. Chem. Soc. 2006, 128, 7428-7429Bian, J.; VanWingerden, M.; Ready, J. M.

H3CO

CH3

O PhO

OH

O

O

O

N

N

Nigellamine A2

H3CO

CH3

O PhO

OH

O

O

O

N

NIntramolecular Pd cat

allylic alkylation

Nozaki-Hiyama-Kishicyclization

Shi Epoxidation

Review of dolabellane diterpenes: Rodriguez, A. D.; Gonzalez, E.; Ramirez, C. Tetrahedron 1998, 54, 11683

Isolated: From Nigella sativa (black cumin); Yoshikawa, M.; et al. Org. Lett. 2004, 6, 869

Biological Activity: Potent lipid metabolism-promoting activity

Development of Pd(π-allyl) Cyclization to Form Tetrasubstituted Olefins

H3CO

CH3

O PhO

OH

O

O

O

N

N

EtO2C

EtO2C

R CH3

CH3

OAcEtO2C

EtO2C

R CH3

CH3

PdH3C

CH3R

EtO2CEtO2C

H3CCH3

R

EtO2CEtO2C

EtO2C

EtO2C

CH3

CH3OAc

RO

R= H, MOM, TBS, Bn, CH2SCH3

Pd(OAc)2 (10 mol%)PPh3 (40 mol%), NaH

>90% conversion

NOT Observed

H3CCH3

CO2Et

CO2Et

RO

Initial Attempts

Reasoned that the problem was due to the electronics of the OR group

Pd

CO2Et

EtO2C

H3C CH3

Stabilized

PdRO

CO2Et

EtO2C

H3C CH3

Destabilized

Solution was to change from CH2OR to a vinyl group

Application of Pd(π-allyl) Cyclization to Nigellamine A2

O

O

2 steps

HO

O

CO2Et

EtO2C

H3C CH3H3C CH3

EtO2CCO2Et

OH3C CH3

O

H3C CH3

CO2Et

EtO2C

PdH3C CH3

PPh2

O

N

t-Bu

CH3MgBr1) TBSCl2) BuLi, ClC(O)i-Pr3) HF•py

O

H3C CH3

HO

OHH3C CH3

1) I2, PPh32) NaCH(CO2Et)237% from lactone

LHMDS, S-LigandPd2(dba)3 (1.25 mol%)

100% conversion, 95 %ee

Ligand

Phosphinooxazoline Ligand: Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett. 1993, 34, 3149

H

Elaboration of Cyclopenane Core

H3C CH3

EtO2CCO2Et

H

O

O

H3C CH3

I

CO2Et

HH

O

O

H3C CH3

CO2Et

HHI210:1 dr

63% over 2 steps

1) hv, (Bu3Sn)22) Bu4NF66% over 2 steps

TIPS SO2CF3

O

O

H3C CH3

I

CO2Et

HH

O

O

H3C CH3

CO2Et

HH

TIPS SO2CF3

O

O

H2C CH3

CO2Et

HHF3CO2S

TIPS

O

O

H3C CH3

CO2Et

HHTIPS SO2

CF3

Proposed Mechansim for Radical Alkynylation

Bu3Sn

Radical Alkynylation: Xiang, J.; Fuchs, P. L. Tetrahedron Lett. 1998, 39, 8597.

Water-Accelerated Methyliodination of Alkyne

O

OH

H3C CH3

HH

OH

O

O

H3C CH3

HH

I

OSi

t-Bu t-Bu

1) DIBAL-H2) NaBH4

1) Cp2Zr2Cl2, AlMe3, H2O (1:3:1); I22) (t-Bu)2Si(OTf)246% over 4 steps(27% recovered prior to methyliodination)

O

O

H3C CH3

CO2Et

HH

Zr[Cp2ZrCl2] H2O

T < 0 °CMe3Al

T> 0 °C

fastslow

MeAl

Cl

Me

MeZr

MeAl

O

Me

Me

R H

R H

Me AlMe2

Me3Al

Proposed Rationale for Water Acceleration

MeAl

OAl

Me

Me Me

no rateacceleration

Water Accelerated Methyliodination: Wipf, P; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068

Completion of the Synthesis of ent-Nigellamine A2

O

OH

H3C CH3

HHH3C

OH

CH3

I

O

H3C CH3

HHH3C

CH3

O OH

H3C CH3H3C

CH3

OH O Ph

O

HOH

1) PdCl2(dppf) (cat) 2) Bu4NF3) Cp2ZrCl2, Al3Me, H2O; I263% over 3 steps

TMSZnBr

H3CO

CH3

O PhO

OH

O

O

O

N

N

O

O

H3C CH3

HH

I

OSi

t-Bu t-Bu

ent- Nigellamine A2

1) PCC (50%)2) CrCl2, Ni(acac)2 (cat) sonication73% yield, d.r. >10:1

1) Dess Martin 2) LiAlH(i-Bu)2t-Bu82% over 2 steps

O

H3C CH3

HHH3C

CH3

O OH

H

1) LiAlH42) PhCOCl51% over 2 steps

1) Shi catalyst, oxone (7:1 chemoselectivity)2) Nicotinic acid, DCC, DMAP51% over 2 steps

O

O O

O

O

H3C

H3CO

H3C CH3Shi Catalyst

25 linear steps 0.6% yield

Shi Epoxidation: Shi, Y. Acc. Chem. Res. 2004, 37, 488; Wang, Z. -X.; Shi, Y. J. Org. Chem. 1998, 63, 3099.LiAlH(iBu)2tBu: Trost, B. M.; Nichimura, Y.; Yammamoto, K.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1328.

Total Synthesis of (+)-Cyanthiwigin UJ. Am. Chem. Soc. 2005, 127, 5334.

Pfeiffer, M. W. B.; Phillips, A. J.

OH

HOH

(+)-Cyanthiwigin U

Isolated: Jamaican sponge Myrmedioderma styx; Hamann, M. T. et al Tetrahedron, 2002, 58, 7809

No biological activity (but many structurally related compounds are active against various cancer cell line,as well as viruses such as HIV-1 and hepatitis B)

Retrosynthetic Analysis of Cyanthiwigin U

O

O

HH

HO

O

OOPiv

Xc

Xc= Chiral Auxiliary

OH

HOH

Diels-AlderCyclization

Two-directionaltandem ROM-RCM

Synthesis of ROM/RCM Precursor

O

OH OPiv

N N MesMes

Ru

PCy3PhCl

Cl

(5 mol%)93 % yield

O

OHOPiv

HO2CH

1) 1,4-dimethylcyclohexadiene TfOH, -78 oC (70%)2) CAN, CH3CN (aq), (82%)

1) LiAlH4, THF (99%)2) (COCl)2, DMSO, Et3N, (84%)

HH

1) , CeCl32) Dess-Martin Periodinane

MgBrH

PivO

O

O

H

O

O

Palomo Chiral Auxiliary: Palomo, C.; Oiarbide, M.; Garcia, J. M.; Gonzalez, A.; Lecumberri, A.; Linden, A. J. Am. Chem. Soc. 2002, 124, 10288

ROM/RCM to Form Desired Tricycle

N N MesMes

Ru

PCy3PhCl

Cl O

O

HHH

O

O

RuLnO

OHH

RuLn

O

OHH

HO

O

O

O

HH

ring openingmetathesis and/or

LnRu

OO

O

O

HH

RuLn

ring closingmetathesis

Previous work by Phillips: Minger, T. L.; Phillips, A. J. Tetrahedron Lett. 2002, 43, 5357.First example of ROM-RCM stradegy in total synthesis: Stille, J. R.; Grubbs, R. H. J. Am. Chem. Soc. 1986, 108, 855.

Completion of the Total Synthesis of Cyanthiwigin U

O

O

HHOHH

HO

H

HHHO

H

OH

HH O

O

HH OHO

H3C

LiAlH4, 92%(dr= 10:1)

i-PrLi, CeCl3

PCC, CH2Cl2 90% (over 2 steps)

MeLiquant. (dr= 9:1)

Cyanthiwigin U12 steps from Piv-ester

17% overall yield

Dauben oxidation: Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682.

Total Synthesis and Absolute Stereochemical Assignmentof (+) and (-)-Galbulimia Alkaloid 13J. Am. Chem. Soc. 2006, 128, 8126.

Movassaghi, M.; Hunt, D. K.; Tjandra, M.

Isolated from the bark of Galbulimima belgraveana: Taylor, W. C. et al. Aust. J. Chem. 1967, 20, 1705Biological Activity: Galbulimima Alkaloid 13 has not been tested but Himacine is a potential treatment for Alzheimer's disease McKinney, M. et al. Bioorg. Med. Chem. Lett. 1992, 2, 797; 1995, 5, 61.Previous synthesis of (+/-) Galbulimima Alkaloid 13: Mander, L. N.; McLachlan, M. M. J. Am. Chem. Soc. 2003, 125, 2400.

Retrosynthetic Analysis of Galbulimima Alkaloid 13

Synthesis of Diels Alder Precursor

Br

Br

Me B(OH)2

OTBS

Me

TBSOBr

Me

TBSON

OO

TBSON

OO

TBSON

OO

OHC

Pd(PPh3)4, Tl2CO3, THF, H2O 23 °C

75 %

CuI, K2CO3, oxazolidin-2-one,(MeNHCH2)2, toluene, 110 °C

95%

1) TBAF, THF (95%)2) MnO2, CH2Cl2 (92%)3) TBSOTf, Et3N, CH2Cl2, -78 °C (93%)

Grubb's cat (2nd gen)acrolein, CH2Cl2, 23 °C

85%

Use of Tl2CO3: Hoshino, Y.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc. Jpn. 1988, 61, 3008.Copper Catalyzed amidation: Jiang, L.; Fob, G. E.; Klapars, A.; Buchwald, S. Org Lett. 2003, 5, 3667.

Synthesis of Radical Cyclization Precursor

N

TBSO

O

HOHC

H

O

H

N

Me

HMeCl

toluene, 90 °C82% (>20:1 endo)TBSO

N

OO

OHC

racemic mixture

BuLi, THF -78 °C 85%

Ph2S(OC(Ph)(CF3)2)2, Ph-H81%

N

N

TBSO

H

O

O

H

H

N

N

TBSO

H

O

O

H

H

OH

N

N

TBSO

H

O

O

H

H

(equal mixture of two diastereomers)

Martin sulfurane: Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327.

Cyclizations to form Galbulimima Alkaloid 13 Core

(product of diastereomer not shown)

N

N

TBSO

H

O

O

H

H

1) NBS, NaHCO3, THF 0 °C2) Bu3SnH, AIBN Ph-H, 60 °C 55% yield

1) Et3N•(HF)3, THF2) NaBH4, EtOH, 0 °C 70% yield

(+ diastereomer)

First example of vinyl radical cyclizations: Stork, G.; Baine, N. H. J. Am. Chem. Soc. 1982, 104, 2321.

Completion of the Total Synthesis of Glabulimima Alkaloid 13

ClCO2Bn, Na2CO3, H2O, CH2Cl2

65%

IBX, TsOH•H2O, Ph-H, DMSO, 65 °C

80%

1) TMSI, CH2Cl2, 0 °C2) HCl (aq)3) NaOH (aq) 89%

20 linear steps3% overall yield