The Staunton-Weinreb Annulation SED Group meeting | Guanqun Zhang | 2015.04.21

Steven M. Weinreb •  Brooklyn, NY – May 10, 1941 (Age 73) •  Cornell University, A.B. – 1963 •  University of Rochester, Ph.D. – 1967

•  Advisor: Marshall Gates

•  NIH Postdoc Fellow •  Columbia; Gilbert Stork: 1966-1967 •  MIT: George Buchi: 1967-1970

•  Fordham University – 1970 •  Associate professor - 1975

•  Penn State University – 1978 •  Professor of chemistry – 1980 •  Russell and Mildred Marker Professor of Natural

Products Chemistry – 1987

Weinreb, S. M. Acc. Chem. Res. 1985, 18, 16. Weinreb, S. M. Acc. Chem. Res. 2002, 36, 59.

Short, P. C&EN 2005, 83, 65. Weinreb, S. M. Heterocycles 2006, 70, 5.

Early synthetic targets

Franck, R. Heterocycles 2006, 70, 1.

Steve Weinreb

O

ONH

HHO

OMecephalotaxine (1972)

N

NHHO2C

OO

CO2H

CO2H

methoxatin (1981)

N N

OMeMeO

HOH2N

CO2H

O

O

MeO

H2N

streptonigrin (1982)

HN H

N H

HH

HH H

HH

papuamine (1994)

O

O N H

OH

OH

pancracine (1997)

N

OMeMeO

MeOOMe

H

tylophorine (1979)

HO

OH OH OOH

OH

O

OMe OHHolivin ("1984")

MeO

OMe OMe OOH

OH

O

OMe OHH

tri-O-methylolivin (1984)

Tri-O-methylolivin

Convergent synthesis: let’s take the naphthalene apart...

MeO

OMe OMe OOH

OH

O

OMe OHH

OMe

MeO

OMe

O

O

OTHP

OMe OH

O

MeO+

OMe

MeO CO2H

Hatch, R. P.; Shringarpure, J.; Weinreb, S. M. JOC 1978, 43, 4172. Todd, J. H.; Starrett, J. E.; Weinreb, S. M. JACS 1984, 106, 1811.

Initial plan:

MeO

OMe OMe OOH

OH

O

OMe OHH

tri-O-methylolivin

MeO

OMe OMe O

CHO MeO

OMe O

CHO MeO

OMe

Cl

linear synthesis: too many steps

Dodd, J. H.; Weinreb, S. M. Tetrahedron 1979, 20, 3593. Hauser, F. M.; Rhee, R. P. JOC 1978, 43, 178.

Kraus, G. A.; Sugimoto, H. TL 1978, 19, 2263.

Weinreb was inspired by four other people:

LDA, THFmethyl acrylate

-78 oC68%

O

O

SOPh

OH

OH

CO2Me

H

LDA (3.3 equiv)MVK (3 equiv)

THF, -78 oCO

O

CN

O

O

O

85%H

Hauser, 1978 Kraus, 1978

Dodd, J. H.; Weinreb, S. M. Tetrahedron 1979, 20, 3593. Wildeman, J.; Borgen, P. C.; Pluim, H.; Rouwette, P. H.F.M.; van Leusen, A. M. TL 1978, 19, 2213.

Parker, K. A.; Kallmerten, J. L. TL 1979, 20, 1197.

(1) NaH, -56 oC(2) KOH, EtOH, H2O

(3) TFA, TFAA (2:3)(4) HOCH2CH2OH, TsOH, HC(OEt)3

47% over 4 steps

OMe

OMe CN

OMe

OMe

O

CN O O

EtO2C

O O+

NaH (2-3 equiv)

1,2-dimethoxyethane-78 oC78%

O

HTs Ph

Ph

O

+ Ph

O

Phvan Leusen, 1978

Parker, 1979

Dodd, J. H.; Weinreb, S. M. Tetrahedron 1979, 20, 3593. Evans, G. E.; Leeper, F. J.; Murphy, J. A.;Staunton, J. JCS Chem. Comm. 1979, 205 and 406.

Jim Staunton

And this brings us to the Staunton-Weinreb annulation

LDA, THF

-78 oC35%

O

OMe

OMe

MeO

+

OMeO

OMe

FSO3

OMe

MeO O

OOMe

O

OEt

OMe

+ O

O

MeO48% over two steps

(1) LDA, THF, -78 oC

(2) H2CN2

OMe

O

OOMe

Staunton-Weinreb annulation general scheme

•  R1 = R2 = alkyl, Bn, MOM, MEM •  X = usually H or OMe •  Y = CH2 or O

•  o-toluate is preformed with base •  o-toluate anion is bright yellow •  electrophile is added later •  Michael acceptor can be acyclic

or cyclic, esters or ketones

OR1

Me

OR2

O

Y

O

X

+

OR1 OH

Y

OLDATHF

-78 oC rt

It’s a stepwise sequence involving Michael addition followed by Dieckmann condensation and subsequent aromatization

OMe

MeO

OMe

O

O

OMe

O

O

O

MeO

+

- MeOH

Staunton-Weinreb annulation general mechanism

Evans, G. E.; Leeper, F. J.; Murphy, J. A.;Staunton, J. JCS Chem. Comm. 1979, 205 and 406.

LDA-78 oC

OMe

MeO

OMe

OOMe

MeO

OH

OMe

O

O

can be isolated if quenched at -78 oC

can be isolated if quenched at 0 oC

OMe

Me

OMe

O O

MeO

+

OR1 OH OLDATHF

-78 oC rtMeO

Staunton-Weinreb annulation general mechanism

if a leaving substituent is absent, tetralones will be isolated

Evans, G. E.; Leeper, F. J.; Murphy, J. A.;Staunton, J. JCS Chem. Comm. 1979, 406. Mahidol, C.; Tarnchopoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. TL 1989, 30, 3861.

OMe

Me

OMe

O O

+

OMe O

OMe

OLDATHF

-78 oC rt

RR

OMe

OMe

Me

OMe

O O

+

OMe

MeO

OH

O

OLDATHF

-78 oC rtMeO

if the alpha position is saturated, decarboxylation can be done to aromatize

The reaction works great with... variety of o-toluates

N

OBnCO2Ph

N

CO2Ph

Br

NMe2

OBocCO2Ph

OBocCO2Ph

OMeMeO

OBocCO2Ph

N

OBocCO2Ph

S

N

EtO2C

OEtCO2Et

O

O NMe

CO2Et

O

O

Donnor, C. D. Tetrahedron 2013, 69, 3747.

α,β-unsaturated esters/ketones

MeO

O H

H OO

OO

MeO

O H

H OO

OTBS

O H

H OO

OO

8

O OMe

OOH

H

OTMS

OO

OMe

SPh

O

O

MeO

O

O

O

O

Essentials in the nucleophile

CO2Me

OMe

O

OMe

O

OMe

LDA, THF

-78 oC+ S S 34%67% without Ph2S2

Hauser, F. M.; Rhee, R. P.; Prasanna, S.; Weinreb, S. M.; Dodd, J. H. Synthesis 1980, 72, 74.

A methyl ether ortho to the ester group is necessary to stabilize the anion

CO2Et LDA, THF

-78 oC+ S S CO2Me

SPh87%

OMe OMe MeO

OMe

O

MeO

Li

Aryl Substituent effects

CO2MeR

LDA (2 equiv)

-65 oC, THF

CO2MeR + O

O

MeO OTBS

6 steps from aspartic acid

slow warm to rt

30 minO

OTBS

OOH

R

CO2Me0%

CO2MeOMe

46%

CO2MeOMe

MeO<5%

CO2MeOMe

PivO0%

CO2MeO

O0%

CO2MeOMEM

MeO0%

CO2MeOMe

MeO41%

CO2MeOMEM

MeO49%

CO2MeOTBS

MeO0%

CO2MeOMe

OMe

20%

CO2MeOMe

Br"10%"

Tan, N. P.H.; Donner, C. D. TL 2008, 49, 4160.

It’s a three-way balance between steric interactions, electron density on the toluate and the stabilization offered by chelation

Skipping the preformed “enolate”

N

CO2Ph

(1) E(2) LDA, HMPA

-95 -50 oCN

O

OH O OBn

NMe2H

OTBS

N

O76%

CO2Ph

Br(1) E(2) n-BuLi

-100 -70 oCN

O

OH O OBn

NMe2H

OTBSO81%

CO2PhOMe

Br (1) E(2) n-BuLi

-100 -0 oC

NO

OH O OBn

H

OTBSOOMe

NMe2

75%

NO

O O OBn

NH

OTBS

E =

Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel, D. R.; Myers, A. G. Science 2005, 308, 395.

Two additional enolate generation methods...Sn

Hill, B.; Rodrigo, R. OL 2005, 7, 5223.

OMeCO2Et (1) LDA, THF, -78 oC

(2) Bu3SnCl

OMeCO2Et

SnBu3

(1) n-BuLi, -78 oC

(2) E, -78 25 oC (75%)

OMe OH O

60%

O OMe

OOH

H

OTMS 51%

OO

OMe

SPh

47%

O OMe

OOH

H

OTMS 71%

O OMe

OOH

H

OTMS 62%

O

75%

O

74%

O

83%

Two additional enolate generation methods...Si

Aono, M.; Terao, Y.; Achiwa, K. Chem. Lett. 1985, 339.

CO2Me

TMS

CO2Me

R+

CsF, HMPA

60 oC, 3 h

OCO2Me

R

CO2Me

CO2MeR+

CO2Me CO2Me

MeO2C

CO2Me

CO2Me

CO2Me

O

OHCO2Me

17%

CO2Me

CO2Me21% CO2Me

CO2Me

15%CO2Me

CO2Me

CO2Me

28%CO2Me

OHCO2Me

41%

CO2Me

OCO2Me

41%

CO2Me 0%CO2Me

OH

14%O CO2Me

33%O

CO2MeMeO2C

Ph

OCO2Me

0%PhCO2Me

CO2Me 70%CO2Me

CO2MePh

O OH

0%

O CO2Me

26%

O

OHCO2Me43%

CO2Me

Two additional enolate generation methods...Si

Xiang, J.-N.; Nambi, P.; Ohlstein, E. H.; Elliott, J. D. Bioorg. Med. Chem. 1998, 6, 695.

CO2Me

TMS

MeO2C CO2Bn

OO

one step+

O

O

OCO2Me

CO2Bn

CO2Me

TMS

MeO2C CO2Bn

OO

CsF, HMPA

60 oC+

CO2Me

O

OCO2Me

CO2Bn

60%

(1) H2, Pd/C

(2) 150 oC

CO2Me

O

O

CO2Me

96%overtwosteps

NaOMe, MeOH, THF

O

O

OCO2Me

quant.

Acyclic Michael acceptor are hit/miss and generally don’t work well

Characteristics of electrophiles

CO2MeOMe

MeO MeO R

OMe

O

+LDA, THF

-78 oC

OMe

MeO

OH

R

O

OMe R = Me 50%R = OMe 0%

Dodd, J. H.; Garigipati, R. S.; Weinreb, S. M. JOC 1982, 47, 4045. Tarnchopoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Synthesis 1986, 785.

CO2MeOMe

R2

OMe

O

+(1) LDA, THF, -78 0 oC

(2) HCl, MeOH, reflux

OMe

R1

O

R2

R1 = R2 = H 41%R1 = H, R2 = Me 40%R1 = Me, R2 = H 52%R1 = R2 = Me 51%R1

Yields aren’t so great

A “cyclic” Michael acceptor

Mahidol, C.; Tarnchopoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. TL 1989, 30, 3861.

OH OH

OHOH

CO2MeOMe

CO2MeMeO2C + 2 eq.

OH OMe

OHOMe

LDA (2 equiv)

THF, -78 oC

CO2MeMeO2CCO2Me

OMe

CO2MeCO2Me

OMe OLDA, -78 oC rt

80%

CO2MeCO2Me

OMe O60%

DDQ, dioxane

reflux

(1) NaOH, EtOH, THF

(2) Me2SO4, K2CO3CO2Me

OMe OMe48% over two steps

500 oC, 0.01 torrCO2Me

OMeOMe 92%

CO2MeOMe

LDA, -78 oC rt74%

O OMe

OMeOMe

CO2Me(1) NaOH (aq.), MeOH, dioxane(2) (MeO)3CH, TsOH, MeOH

(3) DDQ, PhH(4) BCl3, DCM 57% over 4 steps

Applications of this annulation in natural product synthesis

O

MeO

OH OH O

CO2Me

semiviriditoxin

MeO

OH OH O

(R)-atrochrysone

OH

O

OO

O

OO

neojusticidin B

FtsZ inhibitor; broad spectrum antibiotic activity against gram-positive pathogens

A family of anthranoids, which has displayed anti-bacterial, anti-malarial, and insect antifeedant activities

Interesting skeleton for organic synthesis

Synthesis of semiviriditoxin

O

MeO

OH OH O

CO2Me

HO2C CO2H

TBSO

CO2Me

OH

OTBS

NH2O(1) NaNO2, H2SO4, KBr, H2O, 0 oC, 4 h (91%)

(2) BH3-Me2S, THF, -30 oC to rt, 18 h (97%)

(3) K2CO3, DCM, 72 h (96%)(4) TBSCl, imidazole, DCM, 4 h (98%)

methyl propiolaten-BuLi, BF3-Et2O

THF, -78 oC, 30 min (72%)

O

O

MeO OTBS

NaOMe, MeOH, 16 h

(80%)

OMe

MeO

OMe

O

+LDA, THF, -60 oC, 30 min

(36%)

O

MeO

OMe OH O

OTBS

(1) THF, 10% HCl, 16 h(2) PhI(OAc)2, TEMPO, DCM, 20 h(3) NaClO2, tBuOH, H2O, NaH2PO4, 3 h

(4) MeOH, conc'd H2SO4, 16 h(5) BCl3, DCM, 6 h44% over 5 steps

Donner, C. D.; Tan, N. P.H. Tetrahedron 2009, 65, 4007.

Synthesis of atrochrysone

OH

MeO2C CO2Me

OH

MeO2C CO2H

OTBDMS

MeO2C CO2TBDMS

pig liver esterase

pH 8, 92 %

TBDMS-OTf, lutidine

DCM, 0 oC to rt86%

Muller, M.; Lamottke, K.; Low, E.; Magor-Veenstra, E.; Steglich, W. JCS Perkin Trans 1 2000, 2483.

MeO

OH OH O

OH

+OMe

MeO

OMe

O(1) LDA, THF, -78 oC (25%)

(2) HF, MeCN (78%)

OTBDMS

CO2TBDMSMeO

OMeO

OTBDMS Tebbe reagent, THF

-78 oC, 30 min, then rt, 1 h61-85%

(1) K2CO3, MeOH(2) Tf2O, DMAP, DCM

40-80% over two steps

Synthesis of neojusticidin B

Kobayashi, K.; Maeda, K.; Uneda, T.; Morikawa, O.; Konishi, H. JCS Perkin Trans 1 1997, 443.

CO2Et

+ O

O

O

O (1) LDA, THF, -78 oC

(2) p-cymene, 10% Pd/C, reflux

OH

O

OOH

OO

O

O

CO2Et

+ O

O

O

O

OO

notattempted

The molecule in hand...

Feng, Y.; Majireck, M. M.; Weinreb, S. M. ACIE 2012, 51, 12846.

NH

N

CO2Me

N

H

OH

O

TMSEO2C Ts

NH CO2Me

TMSEO2CO 2 equiv LiHMDS, THF, -78 oC

NCO2Me

TMSEO2CO

TsN

NHO

Cl-HCl

NCO2Me

TMSEO2CO

NH CO2Me

TMSEO2CO

TsN

NO

+

NH

NH

CO2Me

HO

H

O

alstilobanine A

Staunton-Weinreb Annulation

•  Discovered Independently by Staunton and Weinreb in 1979 for synthesizing linear polycycles

MeO

OMe OMe OOH

OH

O

OMe OHH

OMe OMe

MeO

OHCO2Et

OMe

MeO

OMe

O

O

OMe

O OMe

MeO

O

OMe

O

O

OMe

MeO

OMe

O O

O NMe

CO2Et

O

O

CO2MeMeO2CO

O

MeO

•  Tandam Michael addition, Dieckmann condensation followed by optional aromatization

•  ortho-toluates

•  Generally requires an ether group ortho to ester for anion stabiliztion

•  ...unless the Anion is generated in situ by lithium-halogen exchange

•  cyclic esters and ketones are generally better electrophiles

OMeCO2Et

CO2Ph

Br

still acyclic

What happened to Hauser, Kraus, van Leusen, and Parker?

Supposingly, this should be the beginning of this part of history

Frank Hauser

O

OMe

OH

O OMe OOMe

OH

O

CO2H

LDACO2, THF

-78 oC

(1) Ac2O, py(2) NaOH, H2O

(3) Ac2O, HClO4

ethyl bromoacetateZn, PhH

refulx

90% 68% over 3 steps

73%

OMe OH

OEt

O (1) KOH, Me2SO4(2) H2O

OMe OMe

OH

O

then on and on for longer polycyclic chains

Hauser, F. M.; Rhee, R. JACS 1977, 99, 4533.

(Stabilized) phthalide nucleophiles

Frank Hauser

O

O

SO2Ph

CO2H

O

(1) PhSH, PhH, reflux

(2) mCPBA, DCM87% over two steps

Hauser, F. M.; Rhee, R. JOC 1978, 43, 178.

One oxidation state higher than the Staunton-Weinreb version

LDA, THFmethyl acrylate

-78 oC68%

O

O

SOPh

OH

OH

CO2Me

LDA, THFmethyl acrylate

-78 oC86%

OH

OH

CO2Me

OCO2Me

O

SO2Ph

Synthesis of neojusticidin B

Kobayashi, K.; Maeda, K.; Uneda, T.; Morikawa, O.; Konishi, H. JCS Perkin Trans 1 1997, 443.

+O

O

O

O

OH

OO

O

O

not attempted

CO2EtO

O

OO

LDA, THF, -78 oC

O

OOMe

OO

O

O

O

OO

O

OO

O

+LDA, THF,

-78 oC

O

OOH

OO

O

OOH

50% over two steps

I2, CHCl3

CH2N2, 0 oC