Utilization of Ring Closing Metathesis in Alkaloid Synthesis

I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines A-C

Suvi T. M. SimilaMartin Group, University of Texas at Austin

Group Meeting, Research September 17, 2007

N

H2O3PO

OH

(-)-FR901483 (1)

MeHN

OMe

N

MeO

CO2Me

N

O

14

15

lundurine A = amide (2) lundurine B = 14,15 (3)lundurine C = amine (4)

Utilization of Ring Closing Metathesis in Alkaloid Synthesis

I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines A-C

Suvi T. M. SimilaMartin Group, University of Texas at Austin

Group Meeting, Research September 17, 2007

N

H2O3PO

OH

(-)-FR901483 (1)

MeHN

OMe

N

MeO

CO2Me

N

O

14

15

lundurine A = amide (2) lundurine B = 14,15 (3)lundurine C = amine (4)

Retrosynthetic Analysis

N NCO2R3

O

BrMg+

3

9

7

CO2R3

N

H2O3PO

OH

MeHN

OMe

N

R1OO

R2O

R2O

MeO2CR2O

TMS CO2Me

3 3

7

3

lactone-lactamrearrangement

RCM

stereoselective

addition to an N-acyl iminium ion

9

NR3O2C

CO2MeR2O

N O

O

R3O2C

R2O

9

7

3

lactonization

Addition of the Allylzinc to the Chiral Imine

N

TBDPSOPd(PPh3)4 benzotriazole

CH2Cl2TrocCl, THF

-78 °C - 25 °C

37% (dr = 45:55)

NHO

TBDPSO

OO

N

TBDPSO

Troc

TBSO

IZnOTBS

HON

HO O

TBDPSO3

11

N

RO

TBDPSO3

11 PhOMe

Simila, S. T. M.; Martin, S. F. J. Org. Chem. 2007, 72, 5342.

Grubbs II

CH2Cl2, 20 h

90% (dr = 45:55)

N

TBDPSO

Troc

OTBS

H N

TBDPSO

Troc

H

OTBS+

H HnOE

nOEH H

33

1112

Model studies: Simila, S. T. M.; Reichelt, A.; Martin, S. F. Tetrahedron Lett. 2006, 47, 2933.

Weinreb’s ResultsOvershadowing Our Endgame

Weinreb. et al. J. Org. Chem. 2006, 71, 2046.

HON

TIPSO O

N

TIPSO O

Ph Ph

LDA

Davisoxaziridine

60% useless intermediate;cannot remove N-Bn efficiently

HONBoc

O

NBoc

ONaHMDS

Davisoxaziridine

98%

OTIPS OTIPS

BnONBoc

OMe

OTIPS1) LAH2) Sc(OTf)3

MeOH

3) BnBr, NaH

73%

BnONBoc

OTIPS

PhOMeArMgCl

TiCl4

87% (dr 5:4)

N

TIPSO

Boc

O

N

TIPSO

Boc

ONaHMDS

Davisoxaziridine

53%

OH

N

TIPSO

Boc

OOBn

N

TIPSO

Boc

OBnPhOMe

ArMgCl

then NaCNBH3

62% (dr ~3:1)

BnBr

NaH

69%

incorrect stereoisomer

SummaryPart I

• A new route to azaspirane core structure of FR901483 was developed via a nucleophilic addition to an acyl iminium ion followed by a ring-closing metathesis

• Lactone-lactam rearrangement gave the azatricyclic core structure of FR901483 • 1-Ethylallylcarbamate protecting group and its cleavage was developed

• Allylzinc reagent was developed and it was successfully added to the chiral imine, however with lack of diastereoselectivity that persuaded us to divert our initial studies toward (-)-FR901483

N

NMeO

CO2Me

O

lundurine A

14

1516N

NMeO

CO2MeN

NMeO

CO2Me

lundurine B lundurine C

II. Toward the Total Synthesis of Lundurines A-CIsolation and Biological Activity

- Isolated in 1995 from the leaf extract of the Borneo species Kopsia tenuis - Biological studies were reported in 2004 - Lundurine B is cytotoxic against B16 melanoma cells (in vitro); 2.8 µg/mL

- Unique hexacyclic core containing dihydroindole-cyclopropane moiety

- No reported total syntheses to date

Kam, T. S.; Yoganathan, K.; Chuah, C. H. Tetrahedron Lett. 1995, 36, 759.Kam, T. S.; Lim, K.; Yoganathan, K.; Hayashi, M.; Komiyama, K. Tetrahedron 2004, 60, 10739.

N

NMeO

CO2Me O OtBu

O

N

NMeO

CO2Me O

O

N2N

NMeO

CO2Me

O

RCM

N

N

MeO

MeO2C

O

OOtBu

lundurine A (1)lundurine B = 14,15 (2)lundurine C (3)

amide reduction

olefin reduction

2

316

16

14

1516

RCM

cyclopropanation

Retrosynthetic Analysis

N

NH2MeO O

HO

O

Ugi 4CC

NC

N

N

MeO

MeO2C

O

OOtBu

R R

R = masked divinyl moiety

16

+ +

+

CO2Me

Retrosynthetic Analysis

N

H2N

MeO

CO2MeO

OtBu

O

+

reductive amination

thenCl

O

Synthesis of the Ugi Components:2-Vinyltryptamine

N

MeO HNO

A, Pd(PPh3)4LiCl, Na2CO3 (aq)

PhCH3/EtOH, 80 °C

87%

N

MeO HNO

NH

MeO HNO

1) Py·HBr3, THF/CHCl32) Boc2O, DMAP

90% (2 steps)

BO

BO

BO

NH

MeO NH2

requisite Ugi component

KOH, EtOHNa2S2O4,

A

Br

Boc

Boc

·pyr

Trivinylboroxane: O’Shea, et. al. J. Org. Chem. 2002, 67, 4968.

Synthesis of the Ugi Components:Masked Divinylketone

PhSH, PhMe70 °C, 24 h

79%

O+ HNMe2·HCl + (CH2O)n

AcOH, 90 °C

40%

O O

Me2N NMe2

NMe

OTsCl, PhCH3

100 °C

then DIPEA 100 °C

30%

NMe

O

Ts

PhSK, PhCH3

20%

O

PhS SPh

S

MeO2C CO2Me

NaOMe, Et2O

>99% S

OCO2Me

S

O

H2SO4,

70%

TMS

i) n-BuLi, 0 °Cii) HCO2Me, THF

0 °C

87%

OH

TMSTMS

10% H2CrO4Acetone

0 °C to 25 °C

80%

O

TMSTMS S

ONaSH·H2ONaHCO3, EtOH

25 °C

79%

MeO2C NRCOR'

R R

MeO2C NRCOR'

·2 HCl

Blicke, F.; McCarty, F. et. al. J. Org. Chem. 1959, 24, 1376.Sapi, J. et. al. Synthesis 1988, 619.Ward, D. E. et. al. J. Org. Chem. 2002, 67, 1618.Detty, M. L. et. al. Organometallics 1992, 11, 2157.Angiolini, L. et al. Polymer 1989, 30, 564.

Successful Ugi Reactions

NH

NH2+CO2H

NH

N

O

HNON

Me

O

NMe

tBuNC, MeOH

99%

NH

NH2+CO2H

NH

N

O

NHO

MeOH

83%

NMe

O

NMe

NC

NH

N

O

OMeO

NMe

AcCl, MeOH55 °C

50%

NC

Oa) NaCN, NH4Cl, Et2O; 61%

b) HCOOH, Ac2O; 44%

NC NHCHOc) tBuOK, THF; 60%

b) triphosgene, DABCO; 35%

Convertible isocyanide: Armstrong, R. W.; Keating, T. A. J. Am. Chem. Soc. 1999, 118, 2574.

NMe

O

Hoffmann type elimination trials of the methyl piperidine ring unsuccessful

Ugi with the Thiopyranone

NH2+

HO2CSPh

S

ON

OPhS

HN

OS NaIO4, MeOH

H2O

90%

N

OPhS

HN

OS O

PhCH3180-200 °C

(W, 300W)

65%

N

O

HN

OS O

O

resubjected to

reaction condX

N

O

HN

OSOH

tBuNC, MeOH

55%

S

O

Sulfoxide eliminations: Rapoport, H. et. al. J. Org. Chem. 1980, 45, 4817. Galons, H. et. al. Synth. Commun, 1991, 21, 1743.

Ugi with Bisthiophenylpentanone

N

O

NHO

MeO

SPh

SPh

NH2PhMe, Dean-Stark

120 °C

or TiCl4, Et3NCH2Cl2

MeO

N SPh

SPh

tBuNC, MeOH

5 days

30%

MeOO

SPhPhS

mCPBA, CH2Cl2-78 -(-20 °C)

96%N

O

NHO

SOPh

SOPh

MeO

N

O

NHO

MeO

CO2H

p-xylene, pyr, W140 °C, 300W

97%

O

PhS SPh

Ugi with the 5-Methoxy-2-vinyltryptamine

N

O

NHO

NH

PhS SPh

MeO

O

SPh

SPh1) PhMe, Dean-Stark

120 °C

2)

tBuNC, MeOH 4 days

NH

NH2MeO

O

O

NHO

SPh

SPh

8%5%

+

+ 55% of A

CO2H

A

Would a protected indole be more soluble?

Protected Tryptamine Piece

NH

OHMeO TBDPS-Cl, imid., DMF

0 - 25 °C

95%NH

OTBDPSMeO NBS, CH2Cl2

71%

NH

OTBDPSMeO

Br

B OBO B O

Pd(PPh3)4, LiClNa2CO3 (aq), EtOH

PhMe, 80 °C

88%

N

OTBDPSMeO

Br

·pyrNaHMDS

MeOCOCl, THF

-78 - 25 °C

79%

N

OTBDPSMeO

CO2Me

TBAF, CH3CO2H

THF, 0 - 25 °C

99%

N

OHMeO

CO2Me

DPPA, DIAD

PPh3, THF 0 - 25 °C

99%

N

N3MeO

CO2Me

PPh3, THF/H2O

55%N

NH2MeO

CO2Me

CO2Me

Ugi with the 5-Methoxy-2-vinyltryptamine

N

O

NHO

NH

PhS SPh

MeO

O

SPh

SPh1) PhMe, Dean-Stark

120 °C

2)

tBuNC, MeOH 4 days

NH

NH2MeO

O

O

NHO

SPh

SPh

8%5%

+

+ 55% of A

CO2H

A

N

O

NHO

N

PhS SPh

MeO

O

SPh

SPh1) PhMe, Dean-Stark

120 °C

2)

tBuNC, MeOH 5 days

N

NH2MeO

CO2H

A

CO2Me

MeO2C

X

the intermediate imine is not soluble in MeOH, CH2Cl2

Synthesis of the RCM Precursor

N

O

NHO

NH

SPh

MeO SPhN

O

NHO

N

SPh

MeO SPh

Boc

N

O

NHO

N

SOPh

MeO SOPh

Boc

N

O

NHO

N

MeO

Boc

Boc2O, DMAPEt3N, CH2Cl2

60%

NaIO4, MeOHH2O

0-25 °C 48%

p-xylene, pyr

W, 140 °C300 W

44%

(0.9 mg)

N

N

Boc

MeOO

NHtBuO

Grubbs II

CH2Cl2

rsm (0.4 mg) + new product by TLC

N

NH2MeO O

HO

O

Ugi 4CC

NC

R R

R = masked divinyl functionality

+ +

+

CO2Me

Execution of the Back-up Plan

N

H2N

MeO

CO2MeO

OtBu

O

+

reductive amination

thenCl

O

N

N

MeO

MeO2C

O

OOtBu

16

Preparation of the Divinylglycine Piece

N

Ph Ph

CO2Me

SOPh

Et3BnN+Cl-, K2CO360 °C, 4 h

N

Ph Ph

CO2Me

SOPh

SOPhN

Ph Ph

CO2Me

SOPh

NH

Ph Ph

H2N CO2Me

CH2Cl2, rt24 h

78%0%

82%

subjected to rxn cond

+

N

Ph Ph

CO2tBu

Br CO2tBuDIEA, MeCNreflux, 12 h

83%

2 x

X

SOPh

Et3BnN+Cl-, K2CO360 °C, 4 h

2 x

N

Ph Ph

CO2tBu

SOPh

SOPhN

Ph Ph

CO2tBu

SOPh

0% 30%

+

Bis-conjugate addition: Galons, H. et. al. Synth. Commun, 1991, 21, 1743.

Preparation of the Divinylglycine Piece

N

Ph Ph

CO2Me

SOPh

Et3BnN+Cl- K2CO3, 60 °C

N

Ph Ph

CO2Me

SOPh

SOPhN

Ph Ph

CO2Me

SOPh

0%0%0%

82%45%57%

+

N

Ph Ph

CO2Me

SOPh

SOPh

Conditions1) LDA, THF, -78 °C 0%2) K2CO3, Et3BnN+Cl- H2O (cat) , 60 °C 19% 3) KOtBu, Et3BnN+Cl-

H2O (1 eq), 60 °C 23%

SOPh

2 x

Conditions18 h W, 4 hW, 4 h (H2O)

Bis-conjugate addition: Galons, H. et. al. Synth. Commun, 1991, 21, 1743.

N

Ph Ph

CO2tBu

SOPh

SOPh

N

Ph Ph

CO2tBu

KOtBuEt3BnN+Cl-

60 °C, 1 h

61%

SOPh2 x

Successful Formation of the RCM Precursors

N

OMeO

N

OHMeO IBX, EtOAc

80 °C

>99%N

NH

MeOCO2tBu

CO2Me CO2MeCO2Me

N

Ph Ph

CO2tBu

SOPh

SOPh

N

Ph Ph

CO2tBu

KOtBuEt3BnN+Cl-

60 °C

61%

SOPh2 x

p-xylene, pyr140 °C

66%

H2N

CO2tBuN

Ph Ph

CO2tBu

citric acid (aq)THF

71%

citric acid (aq)THF

89%H2N

CO2tBu

SOPh

SOPh

H2N

CO2tBu

Na(OAC)3BHCH2Cl2

81%

H2N

CO2tBu

i) Na(OAC)3BHCH2Cl2, 89%

ii) p-xylene, pyr W, 140 °C

69%

SOPh

SOPh

Et3N, CH2Cl2 94%

N

NMeO

CO2Me

O

CO2tBu

COCl

N

NMeO

CO2MeCO2tBu

Br

K2CO3, TBAI, CH3CN W, 80 °C

72%

Tandem-RCM Attemptscatalyst

C6H6, N

N

MeO

MeO2C

O

CO2tBuN

N

MeO

MeO2C CO2tBu

O

A B

CatalystGrubbs II 26 % A 0% B (39% RSM)Schrock 0% A 0% B (99% RSM)Lance 0% A 0% B (99% RSM)

Grubbs II or SchrockC6H6,

N

NMeO

CO2Me

O

CO2tBu

Grubbs II

CH2Cl2, W150 W, 50 °C

orPhMe, 100 °C

N

N

MeO

MeO2C CO2tBu

40% 0%

N

NMeO

CO2MeCO2tBu

N

N

MeO

MeO2C CO2tBu

+

Grubbs IIPhMe, 100 °C

Ru PhPCy3

NMesMesN

ClCl Ru

NN

ClCl

Oi-Pr

Grubbs 2nd Generation catalyst

"Lance"

i-Pr i-PrN

Mo

Ph(F3C)2MeCO

(F3C)2MeCO

Schrock catalystGrubbs catalysts: Grubbs, R. H. Angew. Chem. Int. Ed, 2006, 45, 3760.Lance: Grubbs, R. H. et. al. Org. Lett. 2007, 9, 1589.Schrock catalysts: Schrock, R. R. Angew. Chem. Int. Ed. 2006, 45, 3748.

Possible Explanations for Unsuccessful RCM

N

NMeO

[Ru]N

N

MeO

MeO2COO OO

N

N

MeO

MeO2C

O

CO2tBu[Ru]

OO

Modes of catalyst inhibition: Grubbs, R. H. Acc. Chem. Res, 1995, 28, 446.

Troubleshooting the Functional Group Problems

NH

NMeO

CO2tBu

NH

N

MeO

CO2tBu

Grubbs II

PhMe, W150W, 80 °C, 6 h

~10%

(sm consumed)

Grubbs IIPhMe, W150 W, 80 °C, 3h

N

NMeO

CO2tBuCO2Me

KOH, MeOH

reflux, 18 h

>99%

new spot, sm consumed>>not the desired pdt by MS

Troubleshooting the Functional Group Problems

N

NH

MeOCO2tBu

CO2Me

N

NMeO

CO2tBu

CO2Me

Grubbs IIPhMe

W, 80 °C, 3 hthen 70 °C, 2 d

XN

NMeO

CO2Me

CO2tBu

PhOMe

MeO

Cl

TBAI, K2CO3CH3CN, W

150 W, 80 °C, 3 h

26%

PhOMe

KOH(aq), MeOHreflux, 18 h

84%

NH

NMeO

CO2tBu

PhOMe

Grubbs IIPhMe

W, 80 °C, 3 hthen 70 °C, 24 h N

H

MeON PhOMe

CO2tBu

X

Examples of 8-membered RCM: Martin, S. F. et. al. Tetrahedron Lett. 1994, 35, 691.Lubell, W. D. et. al. J. Org. Chem. 2005, 70, 3838.Rodriguez, J. Angew. Chem. Int. Ed. 2006, 45, 5740.Bennasar, M.-L. Tetrahedron, 2007, 63, 861.

Ts-indole and Cyanide in Place of the t-Butyl Ester

N

OMeO

N

NH

MeOCN

Ts Ts

H2N

CN

Na(OAC)3BHCH2Cl2

45%

H2N

CN

i) Na(OAC)3BHCH2Cl2, 58%

ii) p-xylene, pyr, 140 °C

SOPh

SOPh

N

NMeO

TsCN

Br

K2CO3, TBAI CH3CN, 80 °C

DECOMPOSITION

N

NMeO

TsCN

Br

NaH, TBAI DMF

~50%

//

N

N

MeO

Ts CN

Grubbs II2 x 25 mol%C6D6

LRMS shows correct mass;however not enough material to verify the structure by NMR

Scale-up attempts unsuccessful

Methyl Ester in Place of the t-Butyl Ester

N

OMeO

N

NH

MeOCO2Me

Ts Ts

H2N

CO2Me

i) Na(OAC)3BHCH2Cl2, 58%

ii) p-xylene, pyr W, 140 °C, 50%

SOPh

SOPh

N

NMeO

TsCO2Me

Br

K2CO3, TBAI CH3CN, W 80 °C

79%

N

NMeO

TsCO2Me

Grubbs II2 x 25 mol%

PhMe, rt, 48 h

49%

+ a product that looks like8-membered ring closure; however, mass doesn't match

NH

NMeO

CO2Me NH

NMeO

CO2Me

a) Na, naphthalene (decomp)b) K2CO3, MeOH (saponification)c) Mg, MeOH: (the amine not soluble)

Mg, MeOH

30%

NH

NMeO

CO2Me

Grubbs II

PhMeX

TLC looks terrible...

Methyl Ester in Place of the t-Butyl Ester

N

NMeO

TsCO2Me

Grubbs I2 x 25 mol%

CH2Cl2, uW150W, 50 oC

2 x 3 h

N

NMeO

CO2Me

TsLCMS matches!!!

Reduction of the Ester

N

NMeO

TsCO2tBu

LiAlH4, THF

-20 C to rt

93%

N

NMeO

TsOH

Ac2O, DMAP

Et3N, CH2Cl2

63%

N

NMeO

TsOAc

N

NMeOGrubbs II

PhMe

TsAcO

N

NMeO

TsAcON

NMeO

TsAcO

25 mol% cat, 7 h, rt only A50 mol% cat, 24 h, rt about 1:1 ratio of A and B

A B C

75 mol% cat, 48 h, rt only B; no A nor C

Substrate for 8-Membered Ring Closure

N

NH

MeOCO2Me

Ts

Mg, MeOH

Grubbs II

NH

NH

MeOCO2Me

MOMCl, LHMDS

THF

N

NMeO

CO2Me

MOM

MOM N

N

MeO

MOM

MOM CO2Me

End Game

NH

N

MeO

CO2Me

Pd/C, H2

MeOCOCl N

N

MeO

MeO2C CO2Me

i) H+

ii) iPrCOCl

iii) CH2N2

N

N

MeO

MeO2CO N2

i) CuOTfii) TsNHNH2 NaCNBH2

N

N

MeO

MeO2Clundurine C

NH

N

MeO

CO2Me

Rh, H2

MeOCOCl N

N

MeO

MeO2C CO2Me

i) H+

ii) iPrCOCl

iii) CH2N2

N

N

MeO

MeO2CO N2

i) CuOTfii) TsNHNH2 NaCNBH2

N

N

MeO

MeO2Clundurine A

O O

OO

MeOBF4

N

N

MeO

MeO2Clundurine B

SummaryPart II

• Ugi reactions with cyclic ketones appeared to give better results than acyclic

• Successful route to the RCM precursor via Ugi was developed; however, the low yielding Ugi step steered us to develop another route

• Bisalkylation of an imine, reductive amination and acylation/alkylation provided an efficient route to the RCM precursors

• Preliminary experiments to cyclize 5- and 8-membered rings have been accomplished and further studies are in progress

Acknowledgements

University of Texas at AustinProf. Stephen F. Martin

Martin GroupLab 1

$$$$$$Robert A. Welch Foundation

NIH (GM 25439)RochePfizerMerck

Materia Inc. for catalyst supportProf. Robert H. Grubbs for catalyst support

Woerpel: Inside Addition

Me

inside attack

O

Nu

Nu

O

BnO

Me O

NuMe

OBn

inside attack

Nu

O

Me

BnOOBn

OBnO

Nu

inside attack

Nu

O

OBn

BnOOBn

1,3-cis product

1,3-cis product

1,3-trans product

Woerpel K. A. et al. J. Am. Chem. Soc. 1999, 121, 12208.

Addition to the Acyl Iminium IonWoerpel’s Model

NOR2 R3

outside attack

Nu

NOR2 R3

NuH

H

eclipsed product

NR3

R2O Nu

Stereoselective additions to oxonium ions: Woerpel, K. A. et al. J. Am. Chem. Soc. 1999, 121, 12208.Stereoselective additions to iminium ions: Martin, S. F.; Bur, S. K. Org. Lett. 2000, 2, 3445; Tetrahedron Lett. 1997, 38, 7641.

inside attack

Nu

N

OR2R3

Nu

H

H

staggered product

NR3

R2O Nu

Hydroboration of the Azaspirane

borane fromthe top

borane from the bottom

N

OO

MeO2C

HO N

OO

MeO2C

OH

A B

NN

MeO2C OO O

O

CO2Me

Predicted selectivity:

NCbz

CO2R

OHNCbz

CO2RBHR2

[O]

Development of a New Protecting GroupSubstituted Alloc

NO

HN

O

TMEDA, THF-78 °C, 1 h

MgBr

NH

OOCOCl

R

O O

R

O

O

R

Et3N, DMAPCH3CN, 24 h

R = Me 42%R = Pr 48%R = i-Bu 41%

R = Me 73%R = Pr 87%R = i-Bu 74%

Development of the Deprotection Conditions

HN

OO

O N

Pd(PPh3)4 (20-mol%)nucleophile (5 equiv)

solvent, [0.08 M], 25 °C

Entry Nucleophile Solvent Time (25 °C) Yield

1 Morpholine CH2Cl2/EtOAc 4 h >99%

2 Morpholine CH2Cl2 3 h >99%

3 Pyrrolidine CH2Cl2 1 h >99%

4 Phthalimide CH2Cl2 >18 h N/A

5 Phthalimide K-salt CH2Cl2 >18 h N/A

6 HoBt/DIEA CH2Cl2 >18 h N/A

7 Benzotriazole CH2Cl2 45 min >99%

8* Benzotriazole (1 equiv) CH2Cl2/[0.45 M] 45 min >99%*) 10-mol% Pd(PPh3)4

Allylsilane Addition

Allylsilane acid synthesis: Weiler, L. Can. J. Chem. 1983, 61, 2530.

CO2MeTMS

TMS MgClO

O CO2HTMSNiCl2, THF

0 °C - 25 °C, 6 h

80%

CH3I, K2CO3, DMF

0 °C - 25 °C,1 h

85%

+

NR

CO2MeR-Cl, AgOTfCH2Cl2

-78 °C - 25 °C, 18 h

R = Cbz 42%R = Troc 56%

N

Troc = O

OCl

ClCl

Staudinger/Aza-Wittig/Ugi

N

O

NHO

N

N

NH

PhS

MeO

CO2H

SPh

MeO

NC

O

SPh

SPh

MeOH

CO2Me

NN :PPh3, MeOH

N

NMeO

CO2Me

PPh3

N

NMeO

CO2Me

NN PPh3

N

NMeO

CO2Me

NPh3P N

Staudinger

Aza-Wittig

N

NMeO

CO2Me

SPh

SPhUgi

Towards the Divinyl Functionality

O

OOH

OH

OHHO

TBS-Cl, imidazole

DMF, 0 oC, 30 min

94%

OOTBSTBSO

NH

N

O

NHO

OH

O

mono-oxidized pdt

NH

NH2+HO

O

NH

N

O

NHO

MeOH, 25 °C, 20 h

83%

TBSO OTBS

O

OTBS

OTBS

NC

NH

N

O

NHO

OH

OH

TBAF, THF

0 °C, 30 min

94%NH

N

O

NHO

O

O[O], cond

Conditions:1) Dess-Martin, CH2Cl2, 18 h, 18% mono-ox, 40% rsm 2) Dess-Martin, 2,6-lutidine, CH2Cl2, 17% mono-ox, 45% rsm3) IBX, EtOAc, 80 C, 3 h: mono-ox only; 6 h: unidentified pdt 4) Pyr-SO3, Et3N, DMSO, 18 h, mono-ox & rsm (NMR)

R1N

OR2

NHR3

OOR

ORO

ORRO

R1NH2 + R2CO2H+ R3NC

R1N

OR2

NHR3

OO

O

R1N

OR2

NHR3

O

[O] PPh3