Modern Approaches to Cyclobutanes · R2 R1 R3 R4 R4 R1 R2 R3 ring expansion ring opening (X) n R1 R2 R3 R4 X = CH 2,O, NH N O H SiMe 3 O BF 3·OEt 2 CH 2Cl 2 N O O N O CH OMe 2N 2

Modern Approaches to Cyclobutanes

Ru(bipy)3+

Ru(bipy)32+

Ru(bipy)32+*

i-Pr2NEt

i-Pr2NEt+

h

Ph

O

R

LnEu

Ph

O

R

LnEu

Ph

O

REuLn

O

OO

Ph

S0

S1T1

ISC

T1

sensitizerE

h

R2 R1

R4R3

R4

R1

R2

R3

ring openingring expansion(X)n

R1

R2

R3 R4

X = CH2, O, NH

N

OH

SiMe3

O

BF3·OEt2

CH2Cl2N

O

O

N

OOMeCH2N2

THF

O

N

O

O

OMe

Cyclobutanes as Useful Synthetic Precursors

J. C. Namyslo, D. E. Kaufmann, Chem. Rev. 2003, 103, 1485‐1537.

R2 R1

R4R3

R4

R1

R2

R3


R1

R2

R3 R4

X = CH2, O, NH

N

OH

SiMe3

O

BF3·OEt2

CH2Cl2N

O

O

N

OOMeCH2N2

THF

O

N

O

O

OMe

E. V. Anslyn, D. A. Dougherty, Modern Physical Organic Chemistry, University Science Books, Sausalito, 2006, pp. 100‐109.



R2 R1

R4R3

R4

R1

R2

R3


R1

R2

R3 R4

X = CH2, O, NH

N

OH

SiMe3

O

BF3·OEt2

CH2Cl2N

O

O

N

OOMeCH2N2

THF

O

N

O

O

OMe

S. Faure, S. Piva‐Le Blanc, O. Piva, Tetrahedron Lett. 1999, 40, 6001‐6004.J. C. Namyslo, D. E. Kaufmann, Chem. Rev. 2003, 103, 1485‐1537.

R2 R1

R4R3

R4

R1

R2

R3


R1

R2

R3 R4

X = CH2, O, NH

N

OH

SiMe3

O

BF3·OEt2

CH2Cl2N

O

O

N

OOMeCH2N2

THF

O

N

O

O

OMe

L. M. Reeder, L. S. Hegedus, J. Org. Chem. 1999, 64, 3306‐3311.J. C. Namyslo, D. E. Kaufmann, Chem. Rev. 2003, 103, 1485‐1537.


Cyclobutanes in Natural Products

O

OH H

H

O

Rhodonoid A

OH

H

H

O

HO

Wallichanol B

H

H

OHHO

O

HO

H

Tsugicoline M

HN

O OH

OH

OH

HH

H

H

OO

TripartilactamO CO2Me

H

H

Hippolachnin A

O

O

OMe

H

OO

H

Elysiapyrone A

O

O

O

OHO

HO

Katsumadain C

HO

OH

OH

Dendrowardol C

O

OH

O

GlcO

BzO

Paeoniflorin

CO2H7

HH H H

HHHH

Pentacycloanammoxic acid

Y.‐Y. Fan, X.‐H. Gao, J.‐M. Yue, Sci. China Chem. 2016, 59, 1126‐1141.

Cyclobutanes in Drug Discovery

E. M. Carreira, T. C. Fessard, Chem. Rev. 2014, 114, 8257‐8322.D. C. Blakemore et al., Bioorg. Med. Chem. 2010, 20, 461‐464.

• defined spatial arrangement

• rigid scaffold

• well-defined exit vectors

NH

N

O

MeO

MeO

MeO

MeO

H

H

NH2

CO2H

Lyrica analog

Procoralan

Cyclobutanes in Drug Discovery

E. M. Carreira, T. C. Fessard, Chem. Rev. 2014, 114, 8257‐8322.D. C. Blakemore et al., Bioorg. Med. Chem. 2010, 20, 461‐464.

• defined spatial arrangement

• rigid scaffold

• well-defined exit vectors

NH

N

O

MeO

MeO

MeO

MeO

H

H

NH2

CO2H

Lyrica analog

Procoralan

Overview: Advances in Cyclobutane Synthesis

• [2+2] photocycloadditions

• Lewis acid catalyzed [2+2] cycloadditions

• organocatalyzed [2+2] cycloadditions

• ring closures

[2+2] Photocycloadditons: Mechanistic Considerations

S. Poplata, A. Tröster, Y.‐Q. Zou, T. Bach, Chem. Rev. 2016, 116, 9748‐9815.





via first excited triplet state:h

*

S0 S1

ISC

with sensitizer:

S0

S1T1

ISC

T1

sensitizerE

h

T1





PET mechanism: catalyst catalyst * catalyst

+e

-eh

[2+2] Photocycloadditons: Enantioselective Variants


R. Brimioulle, D. Lenhart, M. M. Maturi, T. Bach, Angew. Chem. Int. Ed. 2015, 54, 3872‐3890.

C. Müller, A. Bauer, T. Bach, Angew. Chem. Int. Ed. 2009, 48, 6640‐6642.







M. M. Maturi, M. Wenninger, R. Alonso, A. Bauer, A. Pöthig, E. Riedle, T. Bach, Chem. Eur. J. 2013, 19, 7461‐7472.


M. M. Maturi, M. Wenninger, R. Alonso, A. Bauer, A. Pöthig, E. Riedle, T. Bach, Chem. Eur. J. 2013, 19, 7461‐7472.


R. Alonso, T. Bach, Angew. Chem. Int. Ed. 2014, 53, 4368‐4371.







R. Brimioulle, H. Guo, T. Bach, Chem. Eur. J. 2012, 18, 7552‐7560.

O O

C (50 mol%)h ( = 366 nm)

CH2Cl2–75 °C, 5 h O O

H

84% yield82% ee

WITHOUT SENSITIZER

NB

OBr3Al

XylXylH

CF3

C



O O

C (50 mol%)h ( = 366 nm)

CH2Cl2–75 °C, 5 h O O

H

84% yield82% ee

WITHOUT SENSITIZER

NB

OBr3Al

XylXylH

CF3

C



O O

C (50 mol%)h ( = 366 nm)

CH2Cl2–75 °C, 5 h O O

H

84% yield82% ee

WITHOUT SENSITIZER

NB

OBr3Al

XylXylH

CF3

C





O O

C (50 mol%)h ( = 366 nm)

CH2Cl2–75 °C, 5 h O O

H

84% yield82% ee

WITHOUT SENSITIZER

NB

OBr3Al

XylXylH

CF3

C


R. Brimioulle, T. Bach, Science 2013, 342, 840‐843.

C (50 mol%)h ( = 366 nm)

CH2Cl2–70 °C, 5 h

84% yield88% ee

WITHOUT SENSITIZER

NB

OBr3Al

XylXylH

CF3

C

N

O

O

N

H

HH

O

O


R. Brimioulle, T. Bach, Science 2013, 342, 840‐843.

N

O

O

M


N. Vallavoju, S. Selvakumar, S. Jockusch, M. P. Sibi, J. Sivaguru, Angew. Chem. Int. Ed. 2014, 53, 5604‐5608.

O O

D (10 mol%)h ( = 350 nm)

PhMe/xylene–78 °C, 2 h O O

H

77% yield92% ee

NH

S

NH

F

F

F

FOH

F3C

F3CD

WITHOUT SENSITIZER



O O

D (10 mol%)h ( = 350 nm)


H

77% yield92% ee

NH

S

NH

F

F

F

FOH

F3C

F3CD

WITHOUT SENSITIZER



O O

D (10 mol%)h ( = 350 nm)


H

77% yield92% ee

NH

S

NH

F

F

F

FOH

F3C

F3CD

WITHOUT SENSITIZER

F3C

O

H

N

S

N

H H

F3C

O

O

F

F

F

F

[2+2] Photocycloadditons: PET Catalysis


M. A. Ischay, Z. Lu, T. P. Yoon, J. Am. Chem. Soc. 2010, 132, 8572‐8574.

O

E (5 mol%)MV(PF6)2 (15 mol%)h ( = 400–700 nm)

MgSO4

MeNO2RT, 3.5 h

O

Ph

HH

MeOMeO

Ph

89% yieldd.r. > 10:1

Ru

N

N

N

NN

N

2

2 PF6

E



O

Ru(bpy)3(PF6)2 (5 mol%)MV(PF6)2 (15 mol%)h ( = 400–700 nm)

MgSO4

MeNO2RT, 3.5 h

O

Ph

HH

MeOMeO

Ph

89% yieldd.r. > 10:1





O

Ru(bpy)3(PF6)2 (5 mol%)MV(PF6)2 (15 mol%)h ( = 400–700 nm)

MgSO4

MeNO2RT, 3.5 h

O

Ph

HH

MeOMeO

Ph

89% yieldd.r. > 10:1


M. A. Ischay, M. E. Anzovino, J. Du, T. P. Yoon, J. Am. Chem. Soc. 2008, 130, 12886‐12887.

O

Ph

O

Ph

F (5 mol%)h ( = 400–700 nm)

LiBF2, i-Pr2NEt

MeCNRT, 50 min

89% yieldd.r. > 10:1

OO

PhPhHH

Ru

N

N

N

NN

N

2

2 Cl

F








J. Du, K. L. Skubi, D. M. Schultz, T. P. Yoon, Science 2014, 344, 392‐396.



Ru(bipy)3+

Ru(bipy)32+

Ru(bipy)32+*

i-Pr2NEt

i-Pr2NEt+

h

Ph

O

R

LnEu

Ph

O

R

LnEu

Ph

O

REuLn

O

OO

Ph

DUAL CATALYSIS

–e




M. Riener, D. A. Nicewicz, Chem. Sci. 2013, 4, 2625‐2629.

H (3 mol%)anthracene (50 mol%)

h ( = 450 nm)

MeCN, RT, 24 h

54% yield

MeO

2

MeO OMe

O

PMP

PMPPh

BF4-

H


M. Riener, D. A. Nicewicz, Chem. Sci. 2013, 4, 2625‐2629.

h

ORGANIC ELECTRON RELAY SYSTEM

O

PMP

PMPPh

O

PMP

PMPPh

O

PMP

PMPPh

anthracene

anthracene

+

+Ar

R

ArR product

*

–e +e

[2+2] Cycloadditions: Lewis Acid Catalysis


E. Canales, E. J. Corey, J. Am. Chem. Soc. 2007, 129, 12686‐12687.



A (10 mol%)

CH2Cl2–78 °C, 3 h

87% yield99% ee

NB

OBr3Al

PhPhH

A

OO

OCH2CF3+

O

O

OCH2CF3H

H



A (10 mol%)

CH2Cl2–78 °C, 12 h

97% yieldd.r. = 97:3

92% ee

O

OCH2CF3+

O

OCH2CF3TIPSO

H

OTIPS


M. R. Luzung, P. Mauleón, F. D. Toste, J. Am. Chem. Soc. 2007, 129, 12402‐12403.

C

Ph

MeO2C

MeO2C

B (3 mol%)AgBF4 (6 mol%)

CH2Cl2, RT

MeO2C

MeO2CPh

H

H

O

O

O

O

Ar2P AuCl

AuClPAr2

B

92% yield95% ee


M. R. Luzung, P. Mauleón, F. D. Toste, J. Am. Chem. Soc. 2007, 129, 12402‐12403.

C

Ph

MeO2C

MeO2C

B (3 mol%)AgBF4 (6 mol%)

CH2Cl2, RT

MeO2C

MeO2CPh

H

H

O

O

O

O

Ar2P AuCl

AuClPAr2

B

92% yield95% ee

LAu+

C

Ph

MeO2C

MeO2C

C

Ph

MeO2C

MeO2C

LAu+

MeO2C

MeO2CPh

HH

AuL

MeO2C

MeO2CPh

H

H


H. Teller, S. Flügge, R. Goddard, A. Fürstner, Angew. Chem. Int. Ed. 2010, 49, 1949‐1953.

C

Ph

MeO2C

MeO2C

C (5.5 mol%)AgBF4 (5 mol%)

CH2Cl2, 0 °C

MeO2C

MeO2CPh

H

H

91% yield99% ee

O

O

ArAr

Ar Ar

MeO

MeO

P

Au

Cl

N

Ph

Ph

C

TsN

C

Ph

D (5 mol%)AgBF4 (5 mol%)

CH2Cl2, RT24 h

TsN

Ph

H

H

86% yield94% ee

O

OP

Au

Cl

N

Ph

Ph

D


H. Teller, S. Flügge, R. Goddard, A. Fürstner, Angew. Chem. Int. Ed. 2010, 49, 1949‐1953.A. Z. González, D. Benitez , E. Tkatchouk, W. A. Goddard, III, F. D. Toste, J. Am. Chem. Soc. 2011, 133, 5500‐5507.

C

Ph

MeO2C

MeO2C

C (5.5 mol%)AgBF4 (5 mol%)

CH2Cl2, 0 °C

MeO2C

MeO2CPh

H

H

91% yield99% ee

O

O

ArAr

Ar Ar

MeO

MeO

P

Au

Cl

N

Ph

Ph

C

TsN

C

Ph

D (5 mol%)AgBF4 (5 mol%)

CH2Cl2, RT24 h

TsN

Ph

H

H

86% yield94% ee

O

OP

Au

Cl

N

Ph

Ph

D


S. Suárez‐Pantiga, C. Hernández‐Díaz, E. Rubio, J. M. González, Angew. Chem. Int. Ed. 2012, 51, 11552‐11555.M. Jia, M. Monari, Q.‐Q. Yang, M. Bandini, Chem. Commun. 2015, 51, 2320‐2323.

C

N

Ts

Ph +

LAuCl (5 mol%)AgNTf2 (4.5 mol%)

CH2Cl2, –70 °C2 h

NTsPh

86% yield92% ee

NBoc

+

C

N

OO

LAuCl (2.5 mol%)AgOTf (5 mol%)

CH2Cl2, –60 °C16 h

NBoc

N

O

O

95% yield93% ee


S. Suárez‐Pantiga, C. Hernández‐Díaz, E. Rubio, J. M. González, Angew. Chem. Int. Ed. 2012, 51, 11552‐11555.M. Jia, M. Monari, Q.‐Q. Yang, M. Bandini, Chem. Commun. 2015, 51, 2320‐2323.


M. L. Conner, Y. Xu, M. K. Brown, J. Am. Chem. Soc. 2015, 137, 3482‐3485.



n-Pr

+C

CO2CH2CF3 E (20 mol%)

CH2Cl2, RT16 h n-Pr

CO2CH2CF3

42% yieldd.r. > 20:1

86% ee

n-Pr n-Pr

+C

CO2CH2CF3 E (20 mol%)

CH2Cl2, RT16 h n-Pr

CO2CH2CF3

41% yieldd.r. > 20:1

84% ee

n-Pr n-Pr

n-Pr



SiMe3

+C

CO2Bn E (20 mol%)

CH2Cl2, RT16 h

CO2Bn

Me3Si

85% yield86% ee

NB

OH

PhPhH

E

CF3

Cl

NTf2


C. M. Rasik, M. K. Brown, J. Am. Chem. Soc. 2013, 135, 1673‐1676.E. M. Rigsbee, C. Zhou, C. M. Rasik, A. Z. Spitz, J. J. Nichols, M. K. Brown, Org. Biomol. Chem. 2016, 14, 5477‐5480.


J.‐L. Hu, L.‐W. Feng, L. Wang, Z. Xie, Y. Tang, X. Li, J. Am. Chem. Soc. 2016, 138, 13151‐13154.

[2+2] Cycloadditions: Organocatalysis


K. Ishihara, K. Nakano, J. Am. Chem. Soc. 2007, 129, 8930‐8931


K. Ishihara, K. Nakano, J. Am. Chem. Soc. 2007, 129, 8930‐8931

i-Pr+

BzO CHO A (10 mol%)

EtNO2, –20 °C48 h

CHOOBz

i-Pr

NH

i-BuN

Bn NH2

·2.6 Tf2NH

A

64% yieldd.r. = 92:8

85% ee


G.‐J. Duan, J.‐B. Ling, W.‐P. Wang, Y.‐C. Luo, P.‐F. Xu, Chem. Commun. 2013, 49, 4625‐4627.


G.‐J. Duan, J.‐B. Ling, W.‐P. Wang, Y.‐C. Luo, P.‐F. Xu, Chem. Commun. 2013, 49, 4625‐4627.

N

Ph

Ph

OTMSPh NR

NR

Ph

N

PhTMSO Ph

PhH

NPh

TMSO Ph

NR

NH

Ph

OTMSPh

H2O

Ph

NR

H

O

Ph

CHO

H2O


L. Albrecht, G. Dickmeiss, F. Cruz Acosta, C. Rodríguez‐Escrich, R. L. Davis, K. A. Jørgensen, J. Am. Chem. Soc. 2012, 134, 2543‐2546.

O

+NO2

Ph

C (20 mol%)N,N-diethyacetamide

H2O, CH2Cl2, RT, 24 h

NO2

Ph Ph

OHC

86% yield99% ee

NH

NH

NH

CF3

CF3

O O

C

Ph



NN

NO

O

O

OHN

Ar

H




G. Talavera, E. Reyes, J. L. Vicario, L. Carrillo, Angew. Chem. Int. Ed. 2012, 51, 4104‐4107.


G. Talavera, E. Reyes, J. L. Vicario, L. Carrillo, Angew. Chem. Int. Ed. 2012, 51, 4104‐4107.

O

+NO2

Ph

B (20 mol%)D (20 mol%)

PhMe, –20 °C, 72 h

Ph

Ph

86% yield91% ee

Ph

OH

OO2N

HOH

NH

Ph

OTMSPh

B NH

S

NH

CF3

F3C

CF3

CF3

D


K. S. Halskov, F. Kniep, V. H. Lauridsen, E. H. Iversen, B. S. Donslund, K. A. Jørgensen, J. Am. Chem. Soc. 2015, 137, 1685‐1691.


K. S. Halskov, F. Kniep, V. H. Lauridsen, E. H. Iversen, B. S. Donslund, K. A. Jørgensen, J. Am. Chem. Soc. 2015, 137, 1685‐1691.

Other [2+2] Cycloadditions

I. Colomer, R. Coura Barcelos, T. J. Donohoe, Angew. Chem. Int. Ed. 2016, 55, 4748‐4752.





MeO75%

OAc MeO70%

Br

MeO73%

CO2H MeO60%

Ring Closures

Ring Closures

M. Chaumontet, R. Piccardi, N. Audic, J. Itce, J.‐L. Peglion, E. Clot, O. Baudoin, J. Am. Chem. Soc. 2008, 130, 15157‐15166.

CO2Me

Br

CO2Me

78% yield

Pd(OAc)2 (10 mol%)(t-Bu3PH)BF4 (20 mol%

K2CO3, DMF140 °C, 1 h

Ring Closures


Pd0

CO2Me

Br

CO2Me

PdII

Br L

CO2Me

PdII

O L

CO32-

Br-

O-O

H

PdIIL

OOH

-O

CO2Me

CO2Me

ox. ad.

ligandexchange

protonabstraction

red. elim.

Ring Closures


CO2Me

Br

CO2Me

78% yield

Pd(OAc)2 (10 mol%)(t-Bu3PH)BF4 (20 mol%

K2CO3, DMF140 °C, 1 h

Ring Closures

H. Ito, T. Toyoda, M. Sawamura, J. Am. Chem. Soc. 2010, 132, 5990‐5992.

PhMe2SiOMs

CuCl (5 mol%), dppp (5 mol%)B2pin2, KOt-Bu

THF, RT, 20 h

PhMe2Si Bpin

93% yieldd.r. > 99:1

SiX "Cu–B"

Cu

Si

B

X

Cu

X

Si B

–CuX

Si B

Ring Closures


PhMe2SiOMs


THF, RT, 20 h

PhMe2Si Bpin

93% yieldd.r. > 99:1

SiX "Cu–B"

Cu

Si

B

X

Cu

X

Si B

–CuX

Si B

Ring Closures



THF, RT, 20 h

PhMe2Si Bpin

76% yieldd.r. = 95:5

PhMe2SiOMs

Me3SiOMs


THF, RT, 20 h

Me3Si Bpin

74% yieldd.r. = 99:1

OMs

Bpin


THF, RT, 20 h

89% yieldd.r. = 95:5

Ring Closures

Y.‐M. Wang, N. C. Bruno, Á. L. Placeres, S. Zhu, S. L. Buchwald, J. Am. Chem. Soc. 2015, 137, 10524‐10527.

Ph

Br

Cu(OAc)2 (5 mol%)A (5.5 mol%)

LiOMe, (EtO)2MeSiHTHF, 50 °C, 36 h

Ph

O

O

O

O

PAr2

PAr2

A

83% yield99% ee

Ring Closures


LCuH

Ar

Br

ArX

H CuL

H

LCuXAr

H

LiOMe

LiBr

LCuOMe

HSiR3

MeOSiR3

syn-hydrocupration

Ring Closures


Ph

Br

Cu(OAc)2 (5 mol%)A (5.5 mol%)

LiOMe, (EtO)2MeSiHTHF, 50 °C, 36 h

Ph

O

O

O

O

PAr2

PAr2

A

83% yield99% ee

Ph

87% yield99% ee

MeO

47% yield97% ee

OMe

MeO

MeO2C

59% yield98% ee

F

79% yield99% ee

S

Ring Expansions

Ring Expansions

J. P. Markham, S. T. Staben, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 9708‐9709.

Ring Expansions


Ring Expansions


Ring Expansions

F. Kleinbeck, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 9178‐9179.

OH

Ph

C

O

Ph

A (2.5 mol%)NaBARF (5 mol%)

DCE, –30 °C, 24 h

76% yield91% ee

MeO

MeO

P

P

AuCl

AuCl

(xyl)2

(xyl)2

A

O

Cy

O

n-hex

O

OBz

O

NPhth

O

Ph

O

CO2Me

85% yield86% ee

89% yield92% ee

99% yield92% ee

97% yield93% ee

95% yield85% ee

99% yield84% ee

Ring Expansions


OH

Ph

C

O

Ph


DCE, –30 °C, 24 h

76% yield91% ee

MeO

MeO

P

P

AuCl

AuCl

(xyl)2

(xyl)2

A

O

Cy

O

n-hex

O

OBz

O

NPhth

O

Ph

O

CO2Me

85% yield86% ee

89% yield92% ee

99% yield92% ee

97% yield93% ee

95% yield85% ee

99% yield84% ee

Ring Expansions


OH

Ph

C

O

Ph


DCE, –30 °C, 24 h

76% yield91% ee

MeO

MeO

P

P

AuCl

AuCl

(xyl)2

(xyl)2

A

O

Cy

O

n-hex

O

OBz

O

NPhth

O

Ph

O

CO2Me

85% yield86% ee

89% yield92% ee

99% yield92% ee

97% yield93% ee

95% yield85% ee

99% yield84% ee

Another Approach

R. Panish, S. R. Chintala, D. T. Boruta, Y. Fang, M. T. Taylor, J. M. Fox, J. Am. Chem. Soc. 2013, 135, 9283‐9286.

Documents

Modern Approaches to Cyclobutanes · R2 R1 R3 R4 R4 R1 R2 R3 ring expansion ring opening (X) n R1 R2 R3 R4 X = CH 2,O, NH N O H SiMe 3 O BF 3·OEt 2 CH 2Cl 2 N O O N O CH OMe 2N 2