stemona alkaloids

19
Stemona Alkaloids 1 Baran Lab Tom Maimone N 1 2 3 5 6 7 8 9 9a The Stemonaceae plant family, which comprises over 30 species, produces a large class of structurally diverse alkaloids featuring a conserved pyrrolo [1,2-a] azepine = perhydroazaazulene = 4-azazaulene nucleus Their roots have been used for centuries in traditional chinese medicince for a variety of purposes including (but not limited to): treatment of bronchitis, tuberculosis, pertussis, as well as anti-parasitic agents Over 80 members have been discovered and many more are likely to be isolated (restriction is limited to only 8 species, mostly from the Stemona genus) N O O I. Stenine Group N O O H H H H H stenine N O O H H H H H H O H O N O O H H HO O H O H N O O HO O H O H H N O O H H O H O H H H H neotuberostemonine 3 11 12 10 tuberostemonine (H 3 = α) tuberostemonine A (H 3 = β) tuberostemonol didehydrotuberostemonine (H 11 = β, H 12 = β, Et = β) bisdehydroneotuberostemonine (H 11 = α, H 12 = α) N O H O H O O H HO oxotuberostemonine N II. Stemoamide Group O N H O O H H O stemoamide N H O H H O O H H O stemonine N H O H H O O OMe neostemonine N O H H O O OMe bisdehydroneostemonine N O H H O O OMe H O H H O protostemonine N O H H O O OMe H O H H O protostemonine N O H H O O OMe O H O didehydroprotostemonin I. Introduction For excellent reviews see (and references therein): Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127. Seger et al. Chemistry & Biodiversity. 2004. 1, 265-279.

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Page 1: Stemona Alkaloids

Stemona Alkaloids

1

Baran Lab Tom Maimone

N

1 2

3

567

8

99a

The Stemonaceae plant family, which comprises over 30 species, produces a large class of structurally diverse alkaloids featuring a conserved pyrrolo [1,2-a] azepine = perhydroazaazulene = 4-azazaulene nucleusTheir roots have been used for centuries in traditional chinese medicince for a variety of purposes including (but not limited to): treatment of bronchitis, tuberculosis, pertussis, as well as anti-parasitic agentsOver 80 members have been discovered and many more are likely to be isolated (restriction is limited to only 8 species, mostly from the Stemona genus)

N

O

O

I. Stenine Group

N

O

O

H

HH

HH

stenine

N

O

O

H

HH

HH

H

OH O N

O

O

H

H

HOOH O

H

N

O

O

HOOH O

H

H

N

O

O

HHOH O

HH

H

H

neotuberostemonine

3

1112

10

tuberostemonine (H3 = α) tuberostemonine A (H3 = β)

tuberostemonol

didehydrotuberostemonine (H11 = β, H12 = β, Et = β)bisdehydroneotuberostemonine (H11 = α, H12 = α)

N OH O

HO

O

HHO

oxotuberostemonine

N

II. Stemoamide GroupO

NH

O

OH

H

O

stemoamide

NH

OH

H

OOH

H

O

stemonine

NH

OH

H

OO

OMe

neostemonine

N

OH

H

OO

OMe

bisdehydroneostemonine

N

OH

H

OO

OMe

HO

H

HO

protostemonine

N

OH

H

OO

OMe

HO

H

HO

protostemonine

N

OH

H

OO

OMe

OHO

didehydroprotostemonin

I. Introduction

For excellent reviews see (and references therein): Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127. Seger et al. Chemistry & Biodiversity. 2004. 1, 265-279.

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Baran Lab Tom Maimone

N

II. Stemoamide Group (Con't)

O

N

OH

HOO OH

OH

H

OMe

isoprotostemonine

N

OH

H

H

OOO

tuberstemoamide

N

OH

HOH

OH

H

OO

stemoninine

NH

OHOH

H

HO

OO

OMe

OH

stemodiol

III. Tuberostemospironine Group

NO

ON

OO

OOH

tuberstemospironine

NO

O OO

H

H

H H

R

NO

OO

H

H

O

O

NO

OO

H

H

O

O

NO

OO

H

H

O NO

OO

HO

MeOH

didehydrocroomine

stemonidine

croomine (R = H)stemospironine (R = OMe)

stemotinine isostemotinine

N

IV. Stemonamine (maistemonine) Group

OO

O

N

OO

O

OMe

Me

N

OO

O

OMe

Me

N

OO

O

OMe

Me

ON

OO

O

OMe

Me

O N

OO

O

OMe

Me

O

H

H O N

OO

O

OMe

Me

HO

O

H

H O

stemonamine isostemonamine

stemonamideisostemonamidemaistemonine oxymaistemonine

Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127.

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3

Baran Lab Tom Maimone

N

O

OO

H

H H

N

V. Parvistemoline

O

OOH

parvistemoline

N

O

OO

H

H H

HO

H

H O

H

parvistemonine

N

O

OO

H

H

HOH O

H

didehydroparvistemonine

VI. Miscellaneous?

NO

OR

HOO

OMe

N

O

H

OOO

OMeR

NH

O

O

OH

H

O

O

H

H O

N

O

OO

H

H

O

OH OH

ONH

O

H

H

OH

O

parvistemoamidetuberostemoninol

tuberostemononeparvistemoninine (R = H)parvistemoninol (R = OH)

stemofoline (R = H)oxystemofoline (R = OH)methoxystemofoline (R = OMe

Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127.

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4

Baran Lab Tom Maimone

II. Biosynthetic ConsiderationsConsider the following carbocyclic skeletons where the C5 units of presumed terpene origin are drawn in bold:

N

O

O

N

O

O

O

O

O

OMe Me

O

O

N

O

O

O

N

O

O

O

O

N

O

O

O

OHN

O

OO

O

Stemofoline protostemonine tuberostemonine

O

stemonine tuberstemonamide tuberostemospironine

This leaves the following fragment unaccounted for:

N

Recall pyrrolizidine biosynthesis:

HN

H2NNH2

N

O

mannich

N

O

homospermidineAn analagous pathway could produce the stemona alkaloids

HN

H2NH2N

spermidineN

O

Thus the following biosynthetic picture emerges:

X

N

O

X

N

[O]

[O]

[O]

N

O

O

OMe

O

O

O

N

O

O

O

O

OMe

stemofoline-CO2

Seger et al. Chemistry & Biodiversity. 2004. 1, 265-279.

Page 5: Stemona Alkaloids

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5

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III. Synthesis

NO

O OO

H

H

H

Croomine(D.R. Williams et al, 1989)

J. Am. Chem. Soc. 1989, 111, 1923 -1925.

MEMO

1

1) n-buLi, THF, ClCO2CH3, -78°C

MEMO

O

O MgBr

OBn

MEMO

H3CO2C

OBn

MEMO

OBn

OOH

MEMO

OBn

O

CO2CH3

MEMO

OBn

O

OBz

MEMO

OBn

OBz

HO N3

OO

N3

H

OH

Ph3POBz

OO

N3

H OBzN3

H CO2CH3

OO

(63%)CuBr DMSTMEDA, Et2O

-78°C23

2)

3) DIBAL, CH2Cl2, -78°C

4) D-DIPT, t-BuOOH, CH2Cl2 -50°C

4

5) Swern, -78°C

(83%)

(95%)

then PPh3=CHCO2CH3-78°C 25°C

(89%)

567

6) LiBH4, MeOH Et2O

5% Rh/Al2O3 H2

(60%)

7) BzCl, Et3N

8) LiN3, DMPU 110°C

(94%)

9) BF3 OEt2, O°C10) LiOH, MeOH

(79%)

11) Swern, then

8 9 10(70-81%)

12) HBF4, MeOH then LiOH, MeOH: H2O

13) Jones reagent14) CH2N2

(78%)OBn

OBn OBn

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Baran Lab Tom Maimone

NO

O OO

H

H

H

Croomine(D.R. Williams et al, 1989)

N3

H CO2CH3

OO N3

H CO2CH3

OO

O

CO2CH3

OO NH

HOO N

HO

H

H O

mechanism ?

N OO

H

H

HO

H

H

O

Stemonine(D.R. Williams et al, 2003)

Org. Lett. 2003, 5, 3361-3364

A Similar iodination cascade was used here as well

O

OCH3

OOTBS N3H

TBSONH

TBSO

MeOOTBSO

H

NH

O

H

H O

TBSO

TBSO

CH3

NH

O

H

H O

O

H

H

HON

HO

H

H O

O

H

H

O

15) BCl3, CH2Cl2, -78°C

16) swern(71%)

1011

17) PPh3, 25°C then NaBH4, MeOH

(90%)18) I2, Et2O, CH2Cl2 25°C

(25°C)

prepared in many steps

1) EtPPh2, PhH, 18h, 25°C, then NaBH4, MeOH

(70%)

12

13

2) I2, Et2O:CH2Cl2, 48 h, 25°C42%

14

4) TBAF5) DMP

(69%)

15

6) Jones Reagent

(68%)

OBn

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NO

O OO

H

H

H

Croomine(Martin et al, 1989)

J. Am. Chem. Soc. 1996, 118, 3299-3300.

OO OTIPSO OTIPSO Br

OO

Br

NH

CO2Me

N CO2MeMeO

Boc

BocO

O

Br

NHH

CO2MeNO

O

H

CO2H

NO

O

HOH

H

O

NO

O

HOH

H

O

NH

O

O

H

H

O

Stemoamide(Jacobi et al, 2000)

J. Am. Chem. Soc. 2000, 122, 4295-4303

racemic synthesis:

O

ClCl

N

OMeO

Cl

N

OMeO

NO

O

1) TIPSOTf, Et3N 0°C 25°C

(99%)

2) s-BuLi, TMEDA THF, 0°C

then Br(CH2)4Br

(83%)3) 5% TIPS-OTf, 0°C

1 2 3

4

5

(32%)

4) TFA

5) 3% Rh/C, H2

EtOAc:EtOH(96%)

6) NMM, DMF, Δ

(74%)7) 3M HBr, 60°CHBr

8) POCl3, DMF

OTIPSO

9) 10% Pd-C/H2

10% HCl/EtOH

(47%)

(85%)

6

7

8

1) Methyl alaninate

2) P2O5

(80%)

3) NaH, then succinimide

(97%)

1 2 3

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Baran Lab Tom Maimone

N

OMeO

NO

ONH

O

O

H

H

O

Stemoamide(Jacobi et al, 2000) N

OMeO

NO

MeO

N

OMeO

NO

H

N

MeO O

NH

O

NH

O

OH

ON

H

O

OH

O

H

rationalize the following by-products formed in the IMDA cascade

NH

O

O

NH

O

OO

MeO2C

NH

O

OO

NH

O

OO

an enantioselective route was alsodeveloped using L-pyroglutamic acid

NH

O

HO2CN

O

R

NH

O

OH

O

3

4) NaBH4, MeOH, H+

(72%)

4

Sn(Bu)3

BF3 OEt2(92%)

Diethylbenzenereflux(55%)

H+

5

6

7

5)

6)

H

NiCl2

NaBH4

73%

8

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Baran Lab Tom Maimone

N

O

O

O

OMeO

N

O

O

O

OMeO

stemonamide isostemonamide

(Kende et al.)

Org. Lett. 2001. 16, 2505-2508

NO O

PMB

N OMeO

OBn

PMBN O

PMB

O

N O

PMB

O

OMe

O

HON

O

O

O

OMeO

N

O

O

O

OMeO

PMB PMBN

O

O

O

OMeO

N

O

O

O

OMeO

PMB PMB

N

O

O

O

OMeO

PMB

OPMB

N

O

O

O

OMeTMSO

PMBN

O

O

O

OMeO

PMB

OPMB OPMB

N

O

O

O

OMe

PMB

OPMB

O

N

O

O

O

OMeO

PMB

OPMB

1) BnO(CH2)3MgBr Et2O, reflux

2) PPTS, MeOH

(90%)1 2

3) H2, 5% Pd/C

O

OMe

TMSOBF3 OEt2

(82%)

3

4

4)

5) swern6) DBU, 25°C

7) swern

5 6

(70%)

1:1 mixtureof 5:6

8) TBDMSOTf, collidine, 0°C

9) Pd(OAc)2 O2, DMSO, 80°C

(93% of 7)(89% of 8)7 8

PMBO

MgBr

5% CuBr DMSTMSCl, HMPA-78°C

9 (74%) 10 (57%) 11 (32%)

10)

12 (67%) 13 (90)

11) KH, Me2N=CH2+CF3CO2

-

(for ketones)

or Me2N=CH2

+CF3CO2-

(for enol ether)

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N

O

O

O

OMeO

N

O

O

O

OMeO

stemonamide isostemonamide

(Kende et al.)

N

O

O

O

OMe

PMB

OPMB

O

N

O

O

O

OMeO

PMB

OPMB

NH

O

O

O

OMe

OH

O

NH

O

O

O

OMeO

NH

O

O

O

OMe

OMs

O

NH

O

O

O

OMeO

OMs

N

O

O

O

OMeO

N

O

O

O

OMeO

NH

O

O

H

Stenine(Hart et al.)

J. Org. Chem. 1990. 55, 6236-6240

O

O

OH

HO

OH

O

NHNH2

OAc

O

NHN(Me)2

12 13

12) CAN, H2O/MeCN

13) RhCl3, EtOH,H2O

(52%)14 15(53%)

OH

14) MsCl, DMAP pyr.

16 17

15) NaH

1 2 3 4

1) Et2AlCl, CHCl3 85°C

(67%)

2) NH2NH2

MeOH

(87%)

3) CH3I, K2CO3

4) AcCl

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NH

O

O

H

Stenine(David Hart et al.)

OAc

O

NHN(Me)2

OAc OH

N

H

H CO2MeHO2C

N

H

H CO2Me

N

H

H CO2MeO

O

N

H

H CO2MeHO

OH

N

H

H CO2Me

Me2N

O

N

H

H CO2Me

OH

O

I

O

N

H

H CO2Me

OH

O

O

N

H

H CO2Me

OH

O

O

4

5) Mesitiylene, Δ6) MeOH

NHCO2Me(94%)

7) 9-BBN/NaBO38) MsCl, Et3N

9) MeLi, THF(89%)

10) Jones reag. acetone

5 6

7

(83%)

11) I2, THF, H2O12) DBU

8

(91%)

13) NaBH4, MeOH t--buOH

(100%)

9

14) t-BuMe2SiCl, Et3N

15) MeC(OMe)2NMe2,

xylene, Δ

10

(93%)

16) I2, THF, H2O

11

(75%)

Sn(n-Bu)3

AIBN, PhH17)

(83%)

12

18) LDA, MeI

(87%)

13

N

H

H CO2Me

EtO2C

O

O

14

19) swern20) Ph3P=CHCO2Et

N

H

H CO2Me

EtO2C

O

O

(91%)

21) Red-Al, CuBr

15

(85%)

OSiMe2t-Bu

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Baran Lab Tom Maimone

NH

O

O

H

Stenine(David Hart et al.)

NH

O

O

H

O

NH

O

O

H

O

S

S

NH

O

O

H

S

S

SNH

O

O

Hfor a similar synthesis with anasymmetric Diels-Alder seeMorimoto et al. Angew. Chem.Int. Ed. Engl. 1996, 35, 904-906.

NH

O

O

H

Stenine(Peter Wipf et al.)

J. Am. Chem. Soc. 1995, 117, 11106-11112

HO

NHCbz

CO2H N

OH

OH

CO2Me

CbzN

OBz

H

CO2Me

CbzHO

N

H

H CO2Me

EtO2C

O

O

22) TMSI, then PhMe, Δ

(85%)

23) OsO4 (cat) NaIO4

24)

SiO2/SOCl2

HSSH

25) Lawesson's reagent

(84%)

26) Raney Ni

EtOH

(75%)

1) PhI(OAc)2, NaHCO3 MeOH, 21 40°C (55%)

15 16 17

18

2) Bz2O3) NaBH4, CeCl3

(89%)

1 2

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Baran Lab Tom Maimone

NH

O

O

H

Stenine(Peter Wipf et al.)

NH

CO2Me

CbzHO

H

NH

CO2Me

Cbz

H

O

NH

CO2Me

Cbz

H

O

(Me)2N

NH

CO2Me

Cbz

H

O

(Me)2N

TIPSO

NH Cbz

H

O

(Me)2N

NH Cbz

H

HO

O

O

N

HO

O

HN

HO

O

H

O

O

4)

N

OBz

H

CO2Me

CbzHO

2

Pd2(dba)3 CHCl3

Bu3P, HCO2H,Et3N

(68%) 3

5) TPAP, NMO

6) KHMDSA,OTf

(46%)4

7) NaBH4, CeCl38) H3CC(OMe)2NMe2, 130°C

(77%)

5

9) AD-mix β, NaIO4

10) NaBH411) TIPS-Cl, DMAP

(76%)

12) LiOH, H2O/THF13) PhOPOCl2, NEt3, PhSeH14) Bu3SnH, AIBN, 130

(70%)N

H Cbz

HO

O

OTIPSOTIPS

15) I2, pH 5.516) Allyl-SnBu3, AIBN

6

78

NH Cbz

HO

O

OTIPS

9

17) LDA, HMPA, MeI18) OsO4, NaIO419) NaBH4, -40°C20)o-(NO2)PhSeCN, Bu3P, H2O2

(47%)

O

21) HF, MeCN22) DMP, NaClO2

23) Pd(OH)2, H2

24) FDPP

10

25) Lawesson's26) Raney-Ni

(73%)(71%)

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Baran Lab Tom Maimone

NH

O

O

H

Stenine

Padwa et al.

Org. Lett. 2002, 4, 1515-1517

N

OTMS

NH

O

MeS

SMe

OAc

N

O

MeS

SMe

OAcO

CO2Me

N

H

MeO2C

O

HO

N

H

O

HN

H

MeO2C

O

H

O

O

I

N

H

O

H

O

O

N

H

H

O

O

1) LDA, then (MeS)2CHCHO, then Ac2O

(80%)1

Cl

O

CO2Me

N

OMeS

CO2Me

O

N

H

MeO2C

O

O

23

4

MeS

DMTSFEt3N

2)3)

(80%)

4) Raney-Ni5) NaBH4, CeCl3

(71%)

5

6) Crabtree's Cat, H27) MsCl, Et3N, DBU

(64%)

6

8) LiOH, H2O9) I2, MeCN

7

10) allyl-Sn(Bu)3, AIBN11) OsO4, NaIO4

O

12) ethane dithiol13) lawesson's

14) Raney-Ni15) LDA, HMPA, MeI

(60%)

(48%)

(67%)8

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Baran Lab Tom Maimone

NH

O

O

H

Stenine

Aubé et al.

J. Am. Chem. Soc. 2005, 127, 15712-15713

P

O O

OMeOMe N3 O

O

N3

N3

TMSO

O

NH

HO

NH

HO

MeO2C

NH

HO

O

NH

HO

O

O

OO

NH

O

O

H

Tuberstemonine

O

H

H O

Wipf et al from the oxidative tyrosine cyclization

N

H

HO

CO2Me

H Cbz

N

H

HO

CO2Me

H

Ph

N

H

CO2Me

H

Ph

O

NaH/ THF (92%) 1

1)2) TMSOTf

(95%)

3)

SnCl4(70% 3:1 dr)

23

4) LHMDS, then BrCH2CO2Me

(73%)

6) LHMDS, MeI

5) NaBH4

(51%)

7) Lawesson's

8) Raney Ni(83%)

8 Steps19% YieldNo PG's

1) TBDMS-Cl, imidazole DMAP2)Et3SiH, Pd(OAc)2, NEt3

3) cinnamyl bromide4) TBAF

(80%)1 23

5) TPAP, NMO6) KHMDS, allyl iodide

(58%)

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Baran Lab Tom Maimone

NH

O

O

H

Tuberstemonine

O

H

H O

(Wipf et al.)

N

H

CO2Me

HO

N

H

CO2Me

HO

N

H

CO2Me

HTBDMSON

H

HTBDMSO

Br OO

OO

OOO

N

H

HHO O

H

H O

N

H

HO

H

H O

O

O

PhSe N

H

HO

H

H O

O

O

N

H

CO2Me

H

Ph

O

3

7) Grubbs

(92%)

4

8) PhSH, Et3N9) (PPh3)3RhCl, H2

10) DBU

(81%)

511) NaBH4, CeCl312) TBDMS-Cl, imid. DMAP

(56%)

6

13) (Me)(OMe)NH HCl Me2AlCl

14) LiDBB

(89%)

15) L-selectride, -78°C

16) TsOH, MeOH

(56%)78

9

17) MeC(OMe)2NMe2,

xylene, Δ18) PhSeCl, MeCN/H2O

(52%)

19) allyl-SnPh320) LDA, HMPA, MeI

21) allyltritylamine, DIEA, toluene, 110°C

(45%)10

22) Grubbs, TsOH, ethylene

23) Pd/C, H2N

H

O

O

H

O

H

H O

Page 17: Stemona Alkaloids

Stemona Alkaloids

17

Baran Lab Tom Maimone

N

O

Ac

O

O

H

MeO

NO

O

O

O

OMe

Isostemofoline(Kende et al.)

J. Am. Chem. Soc. 1999. 121, 7431-7432

OH

OH

O

OMOM

O

OMOM

NN

N

OMOM

Boc

N

OMOM

MeO2C

TBSO

BocN Boc

OMOMO

N Boc

OMOMO

O

N Boc

MOMO

O

O

N Boc

MOMO

O

O

OTIPS N Boc

MOMO

OTIPS

OO

N Boc

MOMO

OTs

OO

1) aq. NaOCl, HOAc

2) MOMCl, EtN(i-Pr)2

(60%)1 2

ON

NMe2

KOEt(80%)

3)

4) Na2S2O4, EtOH, H2O, 90°C5) BOC2O, DMAP

(25%)

4

6)

CO2Me

N2

OTBS

Rhodium octanoate dimer

5

7) Bu4NF8) H2, Pd/C, MeOH,9) H2O, DMSO, 150°C

(90%)

(52%)

6

OO

NaOH, MeOH(90%)

7

8

10)

11) LHMDS, DMPU allyl iodide

(91%)

12) K2OsO4, NaIO4, H2O13) Zn(BH4)2, THF, -10°C14) TIPSCl, imid., DMF

(48%)

15) MeLi (2.2 eq.) DMPU, Et2O -40 °C

16) Bu4NF, THF

17) TsCl, pyr, CHCl3

(85%)

9 10 11(81%)

Page 18: Stemona Alkaloids

Stemona Alkaloids

18

Baran Lab Tom Maimone

N

O

O

O

O

H

MeO

NO

O

O

O

OMe

Isostemofoline(Kende et al.)

N Boc

MOMO

OTs

OO

N Boc

MOMO

OTs

O

HO2C

N Boc

MOMO

OTs

OO

N Boc

MOMO

OTs

O

O

OH

OOMe

N Boc

MOMO

OTs

O

OO

OMe

OH

N

O

OO

OMe

H

O

OH

NO

O

O

O

OMe

NO

O

O

11

18) O3, DMS

(65%)

12

19) i-BuOCOCl, NMM20) NaBH4, MeOH21) DMP

13

22)

OLiO

OMe

14

23) DMP, CH2Cl2

(61%) (56%)

24) CF3CO2H then NaHCO3 (67%)

15

16

25) Tf2O

(12%) (14%)

?

Page 19: Stemona Alkaloids

Stemona Alkaloids

19

Baran Lab Tom Maimone

NO

O

ODidehydrostemofoline (Asparagamine A)

NO

O

O

O

OMeO

OMe

Isodidehydrostemofoline

(Overman et al.)

J. Am. Chem. Soc. 2003. 125, 15284-15285

N

Boc

OMe

OH

BocN

OMe

O2N

OHEtO2C

BocN

OMeOTIPSHO

BocN

OMeOTIPS

O

HN

OMeOTIPS

OH

HIN

MeO

O OTIPS

N

MeO

O

N

MeO

O

MeO2CNMeO2C

O

TMSONOHC

O

TMSO N

O

HO

OMeO

O

HOH

1 2 3

456

7

8 10

1)

CO2Et

O2N

2) H2, Pd/C

3) DBU, then H2, Pd/C4) TIPSOTf, 2,6-lutidine5) DIBAL, PhMe, -78°C

(73%)

6) DMP7) TIPSOTf, Et3N8) O3, DMS

(37%)

9) VinylMgBr, CeCl3

10) TMSI

(85%)

11) (CH2O)n, PhMe/ MeCN,

(94%)

12) TBAF13) SO3 Py, Et3N, DMSO14) Julia olefination

(70%)

15) LDA, ICH2CO2Et16) DBU, PhMe, 130°C

(54%)

17) BBr3; aq. NaOH

18) TMS-imid., 130°C

11 12

19) DIBAL, -78°C20) DMP

21) SiO2 (epim.)54%

O OLi

MeO

then aq. HCl

22)

N

O

O

OMeO

O

H

23) IBX, DMSO

HO

13

N

O

O

O

O

OS

MeOO

N

O

O

O

O

OS

MeOO

25) P(OMe)3Didehydrostemofoline +Isodidehydrostemofoline (65%)

24) CSCl2 DMAP

3.5 : 1

50°C