28 anionic cyclization reactions

Myers

Chem 115

Anionic Cyclization Reactions

Reviews:

Hauser Annulation

Mal, D.; Pahari, P. Chem. Rev. 2007, 107, 1892–1918.
• Annulation reactions of 3-phenylsulfonyl isobenzofuranones with Michael acceptors provide 1,4dihydroxynaphthalenes:

Rathwell, K.; Brimble, M. Synthesis 2007, 643–662.
Mitchell, A. S.; Russell, R. A. Tetrahedron 1995, 51, 5207–5236.

• Anionic Michael-Dieckmann condensation reactions provide a powerful method for the
construction of six-membered rings.

O
O

Generalized Reaction Scheme

O

THF, –78 ºC

SO2Ph

O

OR

1. LDA

O
O

base

OH O

2.

O

CH3

CH3
CH3

>86%

Li SO2Ph

OH

OH O
OR

X

CH3

O

R'

X

X

R'

Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178–180.

• It is generally accepted that the transformation proceeds by an initial Michael addition reaction
followed by Claisen cyclization and elimination of phenylsulfinic acid:
• X = H, CN, SO2Ph, SPh, F, Br, SnR3, P(O)(OR)2, CO2CH3
• Base = LDA, LiHMDS, LiOt-Bu, KOt-Bu, NaHMDS, KHMDS, LiTMP, etc

O
• In a very early example, Schmid showed that esters of homophathalic acid undergo annulation
reactions:

O
LDA

O
SO2Ph

CO2CH3

CH3

CH3

O

OLi

O

CH3

CH3
SO2Ph

SO2Ph

NaOMe, MeOH

OCH3

OCH3

+

O

OH O

O

CO2CH3

CH3

OLi

95 ºC, 50%

CH3
CO2CH3

O
Ph S O
O

OH O

(relative stereochemistry
not determined)

CH3
CH3
OH

OLi O

O

CH3

CH3
LiO SO2Ph

O

CH3

CH3
SO2Ph

Eisenmuth, W.; Renfroe, H. B.; Schmid, H. Helv. Chim. Acta. 1965, 48, 375–379.
Fan Liu

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Chem 115

Anionic Cyclization Reactions
Kraus Annulation

• Conjugate addition of a phenyl sulfoxide derivative followed by intramolecular condensation and
thermal elimination of phenylsulfenic acid gives 1-hydroxynaphthalenes:

2.
CO2Et

CO2Et
1. LDA

O

S

Ph

O

O

S

O

CH3
CH3

O

2.

OCH3 O

O

1. LDA, HMPA

O

THF, –78 ºC

CH3
SOPh

Ph

O

O

O

CH3

Li

THF, –78 ºC

O

• 3-cyanoisobenzofuranones are effective substrates for anionic cyclizations:

Li CN

CN

O
–78 ! 0 ºC
3. K2CO3, MeI
acetone, 60 ºC

OCH3
>50%

66 ºC

Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 26, 2263–2266.
OH O

Comparison of Hauser and Kraus Annulations
CH3

CH3
70%

• While yields for the two methods can be similar in some cases, in other cases the Kraus
annulation was found to be more effective, likely because the cyanoisobenzofuranone nucleophile
is less hindered and more soluble in the reaction medium:

O
O

Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178–180

OH O
O

O
• A closely related method was reported by van Leusen, which involves thermal elimination of
phenylsulfinic acid:

O
CH3O

SO2Ph THF, –78 ºC

O
CH3O

Li SO2Ph

CH3
–78 ! 65 ºC

+

CH3O

OH
35%

CH3

O

OH

CO2Et

O S
Ph
O

O
LiOt-Bu

CO2Et

1. NaH, DME, 23 ºC

CO2Et

CO2Et

2. MeOH, 40 ºC

CO2Et

O
OH O

CH3O
Wildeman, J.; Borgen, P. C.; Pluim, H.; Rouwette, P. H. F. M.; van Leusen, A. M. Tetrahedron
Lett. 1978, 25, 2213–2216.

O

O

76%

O

CH3O2C

O

LiOt-Bu

CN

THF, –60 ºC

CH3

O
CH3O

Li CN

–60 ! 23 ºC

CH3O

O
86% O

CH3

Hauser, F. M.; Combs, D. W. J. Org. Chem. 1980, 45, 4071–4073.
Mal, D.; Patra, A.; Roy, H. Tetrahedron Lett. 2004, 45, 7895–7898.
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Chem 115

Anionic Cyclization Reactions

• In the following example, the Kraus annulation was reported to be a "much cleaner reaction":

• Staunton-Weinreb Annulations
• Staunton and Weinreb showed independently in 1979 that o-toluates are suitable nucleophiles for
anionic cyclization reactions.

CH3O

CH3O

O

CH3O

O

OH O

2. cyclohexenone

1. LDA, HMPA
O

O
THF, –78 ºC

–78 ! 23 ºC

Li SO2Ph

SO2Ph

CH3O

"moderate yield"

OCH3

OH
CH3O

CH3O

CH3O

O

CH3O

O

CH3O

O
1. LDA

OCH3
CH3O

THF, –78 ºC

CH3

O

Li

OH O

2. cyclohexenone

1. LDA, HMPA

CH3O

O

O
THF, –78 ºC

Li CN

CN

OH O

–78 ! 23 ºC

TBSO

OH

"a much cleaner reaction"

80%

CH3O

H

CH3

O

O

TBSO

O
CH3O

CH3
O

H

O

Li, T.-T.; Walsgrove, T. C. Tetrahedron Lett. 1981, 22, 3741–3744.
40%
Dodd, J. H.; Weinreb, S. M. Tetrahedron Lett. 1979, 38, 3593–3596.
• Sammes Annulation

O

• It was shown that a phthalide anion is a suitable reaction partner en route to 1-hydroxynaphthalenes:

CH3O
CH3O

O
O

O

O

CH3O

CH3
O

THF, –40 ºC

CH3O

CH3O

O

LDA

OCH3

OCH3

LDA, HMPA

O

THF, –78 ºC

OCH3

CH3

O

OCH3

CH3O

CH3

Li

–40 ! 23 ºC

Li

58%

CH3O
OH O

O
OCH3

CH3
CH3O

OCH3

BF3•OEt2

CH3

CH2Cl2, 23 ºC

43%

O

CH3O

OH

CH3O

OH O

CO2CH3

O
OCH3

CH3O

CH3

LDA, THF
–15 ºC, 70%

CH3O

CH3

O
O

Broom, N. J. P.; Sammes, P. G. J. Chem. Soc. Chem. Commun. 1978, 162–164.
Broom, N. J. P.; Sammes, P. G. J. Chem. Soc. Perkin Trans. 1 1981, 465–470.

OCH3

Evans, G.; Leeper, F. J.; Murphy, J. A.; Staunton, J. J. Chem. Soc. Chem. Commun. 1979, 205–
206.
Leeper, F. J.; Staunton, J. J. Chem. Soc. Chem. Commun. 1979, 5, 206–207.
Fan Liu

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Myers

Other Nucleophiles

• This annulation reaction can also be done in a single step:

• Phenylsulfenylphthalide, originally reported by Kraus, was also found to be a competent
annulation partner:

O
CH3O

CH3O

O
OCH3

CH3O

Chem 115

Anionic Cyclization Reactions

CH3

O

LDA

CH3

OCH3

THF, –78 ºC

O

CH3

O
O

–78 ! 23 ºC

CH3O

O

Li

O
CH3O
CH3O

OH O

OH O

OEt

1. LDA, HMPA

OEt

O
THF, –78 ºC

SPh

–78 ! 23 ºC

CH3O

Li SPh

CH3O

OH

53%

O
CH3

CH3O

CH3
Kraus, G. A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.; Prugh, S. J. Org. Chem. 1983, 48, 3439–
3944.

79%
• A phenyl ester was employed in a synthetic approach to (+)-pillaromycinone:

O

H

H

OTBS
CH3

CH3O
CO2Ph
CH3

CH3O

CH3O

LDA

H

CO2Ph

THF, –78 ºC

• In the following example, use of the traditional Hauser cyclization substrate, 3-phenylsulfonyl
isobenzofuranone, did not afford the desired product. Using phenylsulfenyl phthalide, however,
provided the desired product in good yield:

O
O

O

Li
CH3O

CH3O

O

O

LiOt-Bu

O

OCH3
OCH3

O

CH3O

CH3

THF, –78 ºC

CH3O

OH

O

H

H

OTBS

CH3

H

O

SPh

Li SPh

CeCl3
–78 ! 26 ºC
62%

CH3O

OH O

O

HO
CH3O

White, J. D.; Nolen, E. G.; Miller, C. H. J. Org. Chem. 1986, 51, 1152–1155.
• In the Stauton-Weinreb annulation reaction, it is imperative that an alkoxy group is present ortho
to the ester group to prevent self-coupling of the nucleophile.

OCH3
OCH3

CH3

Hauser, F. M.; Dorsch, W. A.; Mal, D. Org. Lett. 2002, 4, 2237–2239.
Fan Liu

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Myers

Chem 115

Anionic Cyclization Reactions

• Homophthalide anhydrides were also found to be good cyclization partners:

• Alternatively, homophthalide anhydrides can be used:

O
CO2CH3

Ph

OH
O

O
NaH

O

O

THF, 0 ºC

CO2CH3

CO2CH3

O
O

O
NaH

O
CO2CH3

–78 ! 23 ºC

Ph
Ph

O

O

O THF, 0 ºC

94%

OH O

Ph

O

–78 ! 23 ºC

O

HO2C

Na

Na

O

83%
(relative stereochemistry
not determined)

Tamura, Y.; Sasho, M.; Nakagawa, K.; Tsugoshi, T.; Kita, Y. J. Org. Chem. 1984, 49, 473–478.

Tamura, Y.; Sasho, M.; Nakagawa, K.; Tsugoshi, T.; Kita, Y. J. Org. Chem. 1984, 49, 473–478.
• Synthesis of Cyclohexanone Derivatives (Non-Aromatizing Cyclizations)

• Michael-Dieckmann cyclization of o-toluate anions with Michael acceptors affords cyclohexanone
derivatives:

Swenton Annulation
• Swenton showed that Schmid's anionic cyclization nucleophile (shown on
page 1) can be applied to quinone monoacetals under modified conditions:

OH

CH3O

CH3O

O

O

O

OH

CH3

CO2CH3

LDA

OCH3
CO2CH3

O

THF, –78 ºC

CH3

OCH3
CH3

0 ºC

Li

NaH, THF

+
CO2CH3

CH3O OCH3

25 ºC, 60%

CH3O2C

CH3O

OCH3

CH3O

O

O

O
OCH3

O

CO2CH3

O

CH3

OH

NaH, THF

+
CO2CH3

CH3
CH3O OCH3

HCl, CH3OH
65 ºC, 40%

CH3

Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Synthesis 1986, 785–786.

25 ºC

CH3O2C

CH3
OCH3
OCH3
pTSA, C6H6
80 ºC, 40%

CH3O
N
EtO

CH3O
OCH3

CH3
O

O

O
LDA
THF, –78 ºC

O
OCH3

N
EtO

O

Li
O

OH

CH3O
, EtOH

CH3
CH3O2C

OCH3

Chenard, B. L.; Anderson, D. K.; Swenton, J. S. J. Chem. Soc. Chem. Commun. 1980, 932–933.

–78 ! 24 ºC

Boger, D. L.; Zhang, M. J. Org. Chem. 1992, 57, 3974–3977.
Clive, D. L. J.; Sedgeworth, J. J. Heterocyclic Chem. 1987, 24, 509–511.

OH

O

N
EtO
O

83%

Fan Liu

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Myers

Chem 115

Anionic Cyclization Reactions

• Stereoselective Synthesis of Cyclohexanone Derivatives
• One of the first stereoselective anionic cyclization reactions was reported in 1986 in the synthesis
of olivin trimethyl ether:

• Synthesis of bioxanthracene (–)-ES-242-4:

O

CH3O
O

CH3O

CH3O

1.

O

DME, –78 ºC

O

CH3O

CH3O

LDA

O

CH3

Li

CO2CH3

–78 ! 23 ºC
2. dehydration

O

CH3O

CH3
OMOM

CH3O
CO2CH3

LDA

CO2CH3

THF, –78 ºC

CH3

CH3O

Li

–78 ! 0 ºC

55%

(conditions not specified)

CH3O

CH3O

CH3O

Li
OCH3
O

OCH3

LDA, DMPU

CH3O

OCH3
THF, –78 ºC

CH3O

O
CH3O

OH

CH3O

O

OCH3

O
CH3O

CH3
OH
OH

H3C

CH3O

H

O

O

OH O

CH3

CH3O

CH3

CH3
OMOM
single diastereomer
H

8 steps

CH3
O

O
CH3O

CH3

H3C
CH3O
O
H
H

O
CH3O

O

>51%
CH3O

CH3

OH

(–)-ES-242-4

O
CH3
Tatsuta, K.; Yamazaki, T.; Mase, T.; Yoshimoto, T. Tetrahedron Lett. 1998, 39, 1771–1772.

OH O

OCH3

Franck, R. W.; Bhat, V.; Subramaniam, C. S. J. Am. Chem. Soc. 1986, 108, 2455–2457.

Fan Liu

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Myers

Chem 115

Anionic Cyclization Reactions

• Stereoselective anionic cyclizations were employed in the synthesis of tetracycline antibiotics. An
initial experiment using an organostannane showed that Michael addition occurred with complete
stereoselectivity:

• By using a phenyl ester and LDA for anion formation, Michael-Claisen cyclization occurred in high
yields and with excellent diastereoselectivities:

CH3
H

Et

N(CH3)2
O
N

CH3
Sn(CH3)3

OCH3
CH3O

BocO

CH3

O

O

Li
OCH3

n-BuLi
THF, –78 ºC

CH3O

O

THF, –78 ºC

O

BocO

–78 ! 0 ºC

BnO2CO

O

H

N(CH3)2
O

OBn

O
OTBS

1.

Li
OPh

LDA, TMEDA

OPh

N
O

2. TBSOTf, 98%

OBn

O

OTBS
O

OH N(CH3)2
H3C H H
H
OH
H3C

H

H

NH2

N(CH3)2
HO

O

O
OH O H O

O

TBSO
O
CH3O
H3CO
OTBS

• The stereochemical outcome in the addition step is consistent with a pseudoaxial addition to the
enone, from the "-face opposite the bulky tert-butyldimethylsilyloxy substituent:

2. H2, Pd, THF

BocO

(–)-Doxycycline

OBn

single diastereomer

1. HF, MeCN

MeOH, 90%

N
O

OBn
H3C H H O H N(CH3)2
O
N

N(CH3)2
CH3

O

OTBS

OBn

79%, dr > 20:1

N(CH3)2
Li
OPh

LDA, TMEDA

OPh
BocO

OH O

THF, –78 ºC

O

BocO

–78 ! –10 ºC

H

O

N(CH3)2

O
N

O

Nuc
H

OBn

N(CH3)2
O
N

O

O
OTBS

O
OTBS

(CH3)2N

OBn

H

H

N(CH3)2
OH
NH2

HO

O
OH O H O
Minocycline

Sun, C.; Wang, Q.; Brubaker, J. D.; Wright, P.; Lerner, C. D.; Noson, K.; Charest, M.; Siegel, D. R.;
Wang, Y.-M.; Myers, A. G. J. Am. Chem. Soc. 2008, 130, 17913–1717927.
Carpenter, T. A.; Evans, G. E.; Leeper, F. J.; Staunton, J.; Wilkinson, M. R. J. Chem. Soc. Perkin
Trans. 1 1984, 1043–1051.

O

1. H2, Pd black

(CH3)2N

H

H

N(CH3)2

CH3OH, dioxane

O

N

2. HF, CH3CN, 74%

BocO

OH O

O
OTBS

OBn

83%, dr > 20:1

Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel, D.; Myers, A. G. Science 2005, 308, 395–398.
Sun, C.; Wang, Q.; Brubaker, J. D.; Wright, P.; Lerner, C. D.; Noson, K.; Charest, M.; Siegel, D. R.;
Wang, Y.-M.; Myers, A. G. J. Am. Chem. Soc. 2008, 130, 17913–1717927.
Fan Liu

7


Myers

Chem 115

Anionic Cyclization Reactions

• In the most recently reported route, two consecutive stereoselective anionic cyclization reactions

were used to construct tetracycline antibiotics. In the first cyclization, addition of KHMDS to
deprotonate the final Claisen product was crucial to prevent quenching of the enolate intermediate
by proton transfer from the product or methanol:

CH3O
CO2CH3

CH3O

LDA

CO2CH3
THF, –78 ºC

Li

CH3
N(CH3)2

H3C CH3

OBn

O

O

Na
CH3O

N
O

–78 ! 23 ºC

N(CH3)2
NaHMDS, THF

O
CH3O

LiBr

N
O

O

CH3O

O

OH

H

O

–78 ! –15 °C
80%, dr > 20:1

Li
N(CH3)2

OBn

H

H

O

O
OTBS

O
O

CH3
CH3

O

H

O
O

CH3
CH3

N(CH3)2
99%, single diastereomer

O

O

N

N

–78 ! –15 °C

O

H CH3
H

H

H

H3C CH3

2. KHMDS

CO2Ph

O

H CH3

OBn
H

R

H

H

1.

OBn

H

O

OH

OBn

White, J. D.; Demnitz, F. W. J.; Xu, Q.; Martin, W. H. C. Org. Lett. 2008, 10, 2833–2836.
• In the examples above, an alkoxy substituent must be present ortho to the ester functionality to
prevent dimerization of the nucleophile.

H

H

N(CH3)2
O
N

R
OBn OH O

O
OTBS

OBn

2 steps

tetracycline
antibiotic
candidates

• More than 3000 fully synthetic novel tetracycline antibiotic candidates have been prepared using
stereoselective anionic cyclization reactions.

• This limitation was overcome in tetracycline synthesis by deprotonating the substrate in the
presence of the Michael acceptor:

N

CH3

H

N(CH3)2

+

N

OPh
O

O

O

O
OTBS

OBn

LDA, HMPA

N

H

H

N(CH3)2
O

N

–95 ! –50 ºC

OH O

O
OTBS

OBn

76%, dr > 20:1
Kummer, D. A.; Li, D.; Dion, A.; Myers, A. G. Chem. Sci. 2011, 2, 1710–1718.
Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel, D.; Myers, A. G. Science 2005, 308, 395–398.
Sun, C.; Wang, Q.; Brubaker, J. D.; Wright, P.; Lerner, C. D.; Noson, K.; Charest, M.; Siegel, D. R.;
Wang, Y.-M.; Myers, A. G. J. Am. Chem. Soc. 2008, 130, 17913–1717927.

Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel, D.; Myers, A. G. Science 2005, 308, 395–398.
Fan Liu

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Myers

Chem 115

Anionic Cyclization Reactions

• Another strategy permitting cyclization of aromatic ester substrates lacking ortho substituents

involved in situ anion formation by lithium-halogen exchange, in the presence of the Michael
acceptor:

• A stereoselective anionic cyclization reaction is used in the industrial synthesis of a novel
tetracycline antibiotic candidate:

1. LDA (1.13 equiv)
Et3N•HCl
(0.5 mol%)

F
CH3
H
Br
OPh

N(CH3)2
O

+

O

N
O

O
OTBS

OBn

H

H

N(CH3)2

Bn2N

O

n-BuLi, THF

OPh

OH O

Li
OPh

Bn2N
OBn O

(600 g)

OBn

O
OTBS

2. LiHMDS
(0.11 equiv)

OBn O

N

–100 ! –70 ºC
81%, dr > 20:1

THF, –70 ºC

F

LiHMDS
(0.92 equiv)

H

N(CH3)2
O
N

–78 ! –10 ºC

O
H

N(CH3)2

Br
+
OPh
CH3O

O

O
N

O

O
OTBS

OBn

H

H

N(CH3)2

n-BuLi, THF
–100 ! 0 ºC
75%, dr > 20:1

O
N

CH3O

OH O

OBn
O
OTBS (524 g)

O
OTBS

F

H

O

OBn
N

N
H

Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel, D.; Myers, A. G. Science 2005, 308, 395–398.
Sun, C.; Wang, Q.; Brubaker, J. D.; Wright, P.; Lerner, C. D.; Noson, K.; Charest, M.; Siegel, D. R.;
Wang, Y.-M.; Myers, A. G. J. Am. Chem. Soc. 2008, 130, 17913–1717927.

N(CH3)2
OH
NH2

O
OH OH O H O
Eravacycline

• In the example above, attempted cyclization by direct deprotonation of the corresponding omethylnaphthalene was not successful.

H

O

F

H

H

N(CH3)2

3 steps

O
N

Bn2N
OBn OH O

O
OTBS

OBn

94% (934 g)

• The use of a small amount of Et3N•HCl in the deprotonation step, which provides a source of LiCl,
was found to be crucial in providing consistent and clean cyclization results on a manufacturing
scale.
• Because the presence of excess LDA appeared to promote the formation of byproducts, a weaker
base, LiHMDS, was used as a substitute to deprotonate the acidic proton in the final product and
drive the Claisen reaction to completion.

Ronn, M.; Zhu, Z.; Hogan, P. C.; Zhang, W.-Y.; Niu, J.; Katz, C. E.; Dunwoody, N.; Gilicky, O.;
Deng, Y.; Hunt, D. K.; He, M.; Chen, C.-L.; Sun, C.; Clark, R. B.; Xiao, X.-Y. Org. Process Res.
Dev. 2013, 17, 838–845.

Fan Liu

9


Myers

Chem 115

Anionic Cyclization Reactions
• Synthesis of a dideoxydynemicin analog:

Examples in Synthesis
• Synthesis of 1,4-Dihydroxynaphthalene Derivatives

OH
H
N
OH

t-BuLi

1.
O
LDA

O

THF, –78 ºC

SO2Ph

THF, –78 ºC

Li SO2Ph

CH3O

O

CH3O

O

CH3

O

O
OH

–78 ! 23ºC

O

OCH3
OCH3

OH

• Kraus annulation proved to be ineffective for the synthesis of dynemicin A itself. Instead, a DielsAlder cycloaddition was employed:

OEt

H
N

O

1. KHMDS, THF, –78 ºC
2. TMSCl•Et3N, –20 ºC

TMSO

CH3
CO2Si(i-Pr)3

O
OCH3

TMSO

TMSO

2. m-CPBA, CH2Cl2
0 ºC, 65%

O

H
O

O
TMSO

–20 ! 55ºC, 75%

OTMS

O
CH3O
CO2CH3

2. Methylation
(conditions not
specified)

CH3O

O
LDA

O

O
O

THF, –78 ºC

CH3O

Li SO2Ph

CH3O

SO2Ph
OH O

H
HN

CH3
CO2H

H
O

OH O

TMSO

O
OCH3

CH O
CH3O 3

OH

H
HN

O

2. K2CO3, Me2SO4,
acetone, 65%

1. PhSH, pTSA
C6H6, 80 ºC, 93%

1.

Li CN

CN

OEt

O

O

O

OCH3
OCH3

O

O

O

O

O

O

• Two consecutive anionic annulation reactions were employed for the synthesis of the core
structure of anthracyclines:

CH3

OH
Dynemicin A

MnO2, 3HF•Et3N

H

H
HN

CH3
CO2Si(i-Pr)3
O

O

THF, 23 ºC, 53%

TMSO

OCH3
H

OR OH
R = TMS

CO2CH3
CH3O

OCH3
87%

Hauser, F. M.; Prasanna, S. J. Org. Chem. 1979, 44, 2596–2598.

Myers, A. G.; Fraley, M. E.; Tom, N. J. J. Am. Chem. Soc. 1994, 116, 11556–11557.
Myers, A. G.; Fraley, M. E.; Tom, N. J.; Cohen, S. B.; Madar, D. J. Chem. Biol. 1995, 2, 33–43.
Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D. J. J. Am. Chem. Soc. 1997, 119,
6072–6094.
Fan Liu

10


Myers

Chem 115

Anionic Cyclization Reactions
O

• Synthesis of Trioxacarcin A:

CH3O
1.

CN
O
CH3
MOMO

O

CH3

LiOt-Bu

Li CN

THF, –78 ºC

MOMO

O

H
O
CH3O
CH3O Li

THF, –78 ºC

OCH3 CN

OBn
OTBS

–78 ! 0 ºC

CN

94%

OTBS

O

O
CH3

O

LiHMDS

O

OPMB
CH3O

CH3

CH3O

O

Si(CH3)3 CH
3
nPr
O
CH3
O

O

–78 ! –22 ºC

2. Me2SO4

CH3O

OH O

–22 ! 23 ºC

CH3O
CH3O

Si(CH3)3 CH
3
nPr
O
CH3
O

O

H

OH

OBn
OTBS

Liau, B. B.; Milgram, B. C.; Shair, M. D. J. Am. Chem. Soc. 2012, 134, 16765–16772.

H3C

HO
CH3O
CH3O

O CH3
O
H

OH
O

CH3
CH3
O
HO

CH3 O

H O
OH
O
H

H

O
H

OAc
CH3

CH3O

O
H

H O

• Synthesis of viridicatumtoxin B:

CH3
CH3O
CH3

OBn O

OH

CH3O

1. NaH
+

O

OH O

CH3O OCH3

CH3O OCH3

O

OTBS
MOMO

O

OPMB

O

0 ! 23 ºC
2. DBU
toluene, 65 ºC

OBn O

OH

CSA, CH2Cl2
25 ºC, 99%
trioxacarcin A

CH3
CH3 OCH3
OCH3

CH3
CH3O

Svenda, J.; Hill, N.; Myers, A. G. Proc. Natl. Acad. Sci. 2011, 108, 6709–6714.
Magauer, T.; Smaltz, D. J.; Myers, A. G. Nat. Chem. 2013, 5, 886–893.

OCH3
5 steps

CH3O

OBn O

OBn OH O

OH

(±)
O

O

Si(CH3)3
O
N

PhO
O

OBn

1. t-BuOK
toluene, 25 ºC, 91%

2. TBAF, NH4F
THF, 25 ºC, 86%

CH3
CH3O

CH3
CH3 OCH3
OCH3
H
OBn OH OH O

O
N
OBn

dr = 2 : 1
Nicolaou, K. C.; Nielewski, C.; Hale, C. R. H.; Ioannidou, H. A.; ElMarrouni, A.; Koch, L. G. Angew.
Chem. Int. Ed. 2013, 52, 8736–8741.
Fan Liu

11


Myers
• Synthesis of 1-Hydroxynaphthalene Derivatives

• In Danishefsky's synthesis of dynemicin, a homophthalide anhydride substrate was found to be a
superior cyclization partner, whereas the Kraus annulation failed to provide the desired product.

• Synthesis of tetracycline:

Li CH
3

CH3
LDA

O
O

CH3O

Chem 115

Anionic Cyclization Reactions

OH

• In this synthesis, a series of oxidation reactions provided the anthraquinone of dynemicin A:

O

THF, –40 ºC

H

O

CH3O

NHCbz
OBn

H
N

OBn
O
CH3

OH

OCH3

HO CH3

H

OH O

OBn

OH

CH3O

HO CH3

15 steps

H

OH O

MOMO
O

NHCbz
OBn

OBn
CH3O

O
MOMO

O

O

O

O

O

THF, 0 ºC

MOMO

O

OH

N(CH3)2
OH

O
OH O H O

H

Li

LiHMDS

PhI(OCOCF3)2
THF, 0 ºC

NH2
HO

CO2MOM
O

80%

MOMO

SOCl2, Et3N
CH2Cl2
–30 ºC, 90%

NHCbz
H
OBn

CH3

H
HN

MOMO

CH3
CO2MOM
O
OCH3

(–)-Tetracycline

H

Tatsuta, K.; Yoshimoto, T.; Gunji, H.; Okado, Y.; Takahashi, M. Chem. Lett. 2000, 646–647.

MOMO

O

OH

• Synthesis of a benanomicinone analogue:

CH3O

OCH3
CO2CH3
SOPh

CH3O
Br

CH3O
LiOt-Bu
THF, DMSO

OCH3
CO2CH3
SOPh

CH3O
Br

OCH3

MOMO

OCH3 Li

H
N

CH3
CO2MOM
OCH3
H

O

CH3O

OCH3
OCH3
O

OCH3
OCH3
CH3O
31% (2 steps)

OH O 15% (4 steps)

CH3
CO2H
O

1. air, THF, 25 ºC
2. MgBr2, Et2O
0 ! 25 ºC

OCH3
H
OH O

OH

Dynemicin A

OCH3

CH3O
Br

OCH3
OCH3

MOMO

OH O

O

H
HN

CH3
CO2CH3

Hauser, F. M.; Liao, H.; Sun, Y. Org. Lett. 2002, 4, 2241–2243.

CH3O
1.

CH3
CO2CH3

2. (CH3)2SO4, K2CO3
acetone

Shair, M. D.; Yoon, T.-Y.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1995, 34, 1721–1723.
Shair, M. D.; Yoon, T.-Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem. Soc. 1996,
118, 9509–9525.
Fan Liu

12


Myers

• The Shair group found that a particularly difficult annulation reaction was best carried out using a
benzyl fluoride as the nucleophile:

CH3O
CH3

Chem 115

Anionic Cyclization Reactions

CH3 n Si(CH3)3
Pr O
O
O
O

BnO
H
TBSO

O

OCH3
CH3O
O

CH3O
+
F

H
F
OCH3

O
OCH3
OCH3

OTBS
OBn

+

O
O

O
OCH3

• A bidirectional approach to hibarimicinone: note the use of two different nucleophiles to form the C
and F rings:

O

On

CH3

Pr
Si(CH3)3 CH3

CH3

CH3 n Si(CH3)3
Pr O
O
O
O

O

CH3O
CH3O
OBn

O

BnO
H
TBSO

NC

1. LiTMP, THF, –78 ºC
2. HMDS, –78 ! –35 ºC
3. MgBr2•OEt2

BnO
OCH3

SPh

H

OCH3

OTBS
OBn
O

O

O

CH3
Pr
Si(CH3)3 CH3

On

O

OBn
racemic–atropisomers

–35 ! 0 ºC

LiHMDS, THF, –78 ! 0 °C;
KHMDS, 0 ! 23 ºC
50–59%

CH3
NaHCO3, TFE
H2O, 80 ºC
59% (2 steps)

CH3

F

H

H

H

F

O HO
OCH3
OCH3

OTBS
OBn
O

O

BnO
H
TBSO

O

CH3

O
Pr
Si(CH3)3CH3

On

CH3

OCH3

CH3O
CH
O
Si(CH
)
3
3 3
CH3
nPr
O
OH OBn
O
O
O

BnO
H
TBSO

CH3O
CH3O
Si(CH3)3
CH3
nPr

O
OH O
O
O
O

BnO
H
TBSO

CH3O
CH3O
CH
O
Si(CH
)
3
3
3
CH3
nPr
O
OH O
O
O

OCH3

H

OH O

OCH3
OCH3
OCH3

OTBS
OBn
O

BnO HO
OCH3
OH OBn

H

O

CH3
Pr
Si(CH3)3CH3

On

O

~1.3:1 mixture of 2 separable atropisomers

OTBS
OBn

O

O

SPh
H

DMTSF, DTBMP, MeCN
0 ! 23 ºC

CH3
Pr
CH
Si(CH3)3 3

On

O

2 atropisomers
OCH3
• The electronegative fluorine atom stabilizes the anion and is sterically unencumbered.

CH3
• In the absence of the fluorine atom, Michael addition occurred at –78 ºC but the subsequent
Claisen cyclization could never be driven to completion. The alternative Hauser and van Leusen
substrates did not afford the desired product.
• Addition of HMDS prior to warming quenches excess LiTMP, which prevents substrate
decomposition in the subsequent Claisen condensation step.

Liau, B. B.; Milgram, B. C.; Shair, M. D. J. Am. Chem. Soc. 2012, 134, 16765–16772.

CH3O
Si(CH3)3
CH3
nPr
O
OH OBn
O
O
O

BnO
H
TBSO

C

H

OTBS
OBn

F

BnO HO
OCH3

O

O

CH3
Pr
Si(CH3)3CH3

On

O

OH OBn
atropisomer 1 (75%)
atropisomer 2 (89%)

Liau, B. B.; Milgram, B. C.; Shair, M. D. J. Am. Chem. Soc. 2012, 134, 16765–16772.

Fan Liu

13


Myers

Chem 115

Anionic Cyclization Reactions

Synthesis of Annulation Substrates

PhS

CH3

• Hauser Annulation Substrates

EtO2C

SR

H

O

CO2H

O

1. PhSH, C6H6

THF, –78 ºC
2. PhSSPh (4.4 equiv)

CO2Et

CO2Et
OCH3

1. LDA (3 equiv)

SPh

THF, –78 ºC
2. PhSSPh (2.2 equiv)
–78 ! 23 °C

SPh

SO2Ph

3. TFA, H2O

CO2Et
OCH3

OCH3 O

m-CPBA, K2CO3

OCH3
OCH3

CH2Cl2, 100%

CH3O
CH3O

OCH3
OCH3

O

SPh

O

O

PhO2S

O

95%

SPh

O
O

CH3O
CH3O
SPh

100%

CO2Et

O

Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178–180

TFA, H2O

OCH3
OCH3

PhS

O

CH3

CH3O
CH3O

55%

CH3

OCH3 O

yield not provided

1. LDA (6 equiv)

OCH3
OCH3

O

2. m-CPBA, CH2Cl2

OCH3

EtO2C

CH3O
CH3O

SO2Ph

O

SPh

O

PhS

Hauser, F. M.; Gauuan, P. J. F. Org. Lett. 1999, 1, 671–672.

83%
O
MOMO

Hauser, F. M.; Rhee, R. P.; Prasanna, S. Synthesis 1980, 72–74.

CH3
MOMO

H

NEt2
O

1. PhSO2Na, AcOH
80 ºC, 66%

MOMO

SO2Ph
O

2. MOMCl, DIPEA, DMF
–40 ! 23 °C, 74%

CH3
MOMO

O

Tatsuka, K.; Inukai, T.; Itoh, S.; Kawarasaki, M.; Nakano, Y. J. Antibiot. 2002, 55, 1076–1080.
SPh
O

1. LDA, HMPA

• In the following example, the sulfoxide intermediate underwent Pummerer rearrangement and the
resulting sulfonium ion was trapped by the carboxylic acid:

O

2. PhSSPh
OCH3 O

–78 ! 0 °C, 49%

OCH3 O

O
CH3
O

Kraus, G. A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.; Prugh, S. J. Org. Chem. 1983, 48,
3439–3444.

CO2Et

1. NBS, CCl4
h", 84%
2. PhSH, KOH
EtOH, 97%

O

SPh

O

SPh

4. m-CPBA, CH2Cl2

O

CO2H

5. Ac2O
60% (3 steps)

O
O
O

3. KOH, MeOH, H2O

Hauser, F. M.; Dorsch, W. A. Org. Lett. 2003, 5, 3753–3754.

Fan Liu

14


Myers

Chem 115

Anionic Cyclization Reactions
O
CH3
CO2Et

S

Ph
CN

1. NBS

CHO

2. NaSPh, EtOH

CO2Et

OH

3. NaIO4

1. KCN, HCl

O

yield not provided

Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178–180

OH
OH

H2O, 0 ºC, 77%

CN

2. (COCl)2, C5H5N

O

O

DMF, MeCN
–15 ºC, 82%

O

Freskos, J. N.; Morrow, G. W.; Swenton, J. S. J. Org. Chem. 1985, 50, 805–810.
Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 26, 2263–2266.
SPh

CH3

CN

1. LDA (1 equiv)
CHO

CO2Et
OCH3

THF, –78 ºC
2. PhSSPh (1.1 equiv)

CO2Et
OCH3

1. KCN, NaHSO3

OH
OCH3

OCH3

87%

O

CN
2. SiO2, 50%

O

50% (2 steps)

O

O

Hauser, F. M.; Rhee, R. P.; Prasanna, S. Synthesis 1980, 72–74.

CH3

CN

CN

1. LDA, –78 ºC

O

O

O

CN

CN

• Kraus Annulation Substrates

O

CO2Et
OCH3

3. ClSO2NCO, 30%

1. NBS, (PhCO2)2

CCl4, 80 ºC

2. NaCN, EtOH

CO2Et
OCH3

CCl4, 80 ºC

O
OCH3 O

2. 155 ºC, 49%

80 ºC, 55%

O

2. CO2

1. NBS, (PhCO2)2

O
Kraus, G. A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.; Prugh, S. J. Org. Chem. 1983, 48,
3439–3444.

Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 26, 2263–2266.
O
CHO
CONEt2
OCH3

CH3

CN
NaCN, PTSA

O

THF, H2O
0 ! 23 °C, 95%

Li, T.-T.; Wu, Y. L. J. Am. Chem. Soc. 1981, 103, 7007–7009.

OCH3 O

H
NEt2

CH3
MOMO

CN

O

CH3

1. TMSCN, CH2Cl2
KCN (cat), 18-crown-6

0 ! 23 °C

O
CH3
MOMO

O

2. AcOH, 23 ºC, 77%

Svenda, J.; Hill, N. ; Myers, A. G. Proc. Natl. Acad. Sci. 2011, 108, 6709–6714.
Magauer, T.; Smaltz, D. J.; Myers, A. G. Nat. Chem. 2013, 5, 886–893.
Fan Liu

15