Modern Approaches to Cyclobutanes · R2 R1 R3 R4 R4 R1 R2 R3 ring expansion ring opening (X) n R1...

Modern Approaches to Cyclobutanes

Ru(bipy)3+

Ru(bipy)32+

Ru(bipy)32+*

i-Pr2NEt

i-Pr2NEt+

sensitizerE

ring openingring expansion(X)n

X = CH2, O, NH

BF3·OEt2

CH2Cl2N

OOMeCH2N2

Cyclobutanes as Useful Synthetic Precursors

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

X = CH2, O, NH

BF3·OEt2

CH2Cl2N

OOMeCH2N2

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

X = CH2, O, NH

BF3·OEt2

CH2Cl2N

OOMeCH2N2

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.

X = CH2, O, NH

BF3·OEt2

CH2Cl2N

OOMeCH2N2

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

Rhodonoid A

Wallichanol B

Tsugicoline M

TripartilactamO CO2Me

Hippolachnin A

Elysiapyrone A

Katsumadain C

Dendrowardol C

Paeoniflorin

HH H H

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

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

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

with sensitizer:

sensitizerE

PET mechanism: catalyst catalyst * catalyst

[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.

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.

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

CH2Cl2–75 °C, 5 h O O

84% yield82% ee

WITHOUT SENSITIZER

OBr3Al

XylXylH

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

CH2Cl2–75 °C, 5 h O O

84% yield82% ee

WITHOUT SENSITIZER

OBr3Al

XylXylH

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

CH2Cl2–75 °C, 5 h O O

84% yield82% ee

WITHOUT SENSITIZER

OBr3Al

XylXylH

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

CH2Cl2–75 °C, 5 h O O

84% yield82% ee

WITHOUT SENSITIZER

OBr3Al

XylXylH

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

OBr3Al

XylXylH

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

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

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

PhMe/xylene–78 °C, 2 h O O

77% yield92% ee

WITHOUT SENSITIZER

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

77% yield92% ee

WITHOUT SENSITIZER

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

77% yield92% ee

WITHOUT SENSITIZER

[2+2] Photocycloadditons: PET Catalysis

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

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

MeNO2RT, 3.5 h

MeOMeO

89% yieldd.r. > 10:1

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

MeNO2RT, 3.5 h

MeOMeO

89% yieldd.r. > 10:1

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

MeNO2RT, 3.5 h

MeOMeO

89% yieldd.r. > 10:1

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

F (5 mol%)h ( = 400–700 nm)

LiBF2, i-Pr2NEt

MeCNRT, 50 min

89% yieldd.r. > 10:1

PhPhHH

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+

DUAL CATALYSIS

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 OMe

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

ORGANIC ELECTRON RELAY SYSTEM

anthracene

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

OBr3Al

OCH2CF3+

OCH2CF3H

A (10 mol%)

CH2Cl2–78 °C, 12 h

97% yieldd.r. = 97:3

92% ee

OCH2CF3+

OCH2CF3TIPSO

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

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

CH2Cl2, RT

MeO2CPh

Ar2P AuCl

AuClPAr2

92% yield95% ee

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

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

CH2Cl2, RT

MeO2CPh

Ar2P AuCl

AuClPAr2

92% yield95% ee

MeO2CPh

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

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

CH2Cl2, 0 °C

MeO2CPh

91% yield99% ee

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

CH2Cl2, RT24 h

86% yield94% ee

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 (5.5 mol%)AgBF4 (5 mol%)

CH2Cl2, 0 °C

MeO2CPh

91% yield99% ee

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

CH2Cl2, RT24 h

86% yield94% 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.

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

CH2Cl2, –70 °C2 h

86% yield92% ee

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

CH2Cl2, –60 °C16 h

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.

CO2CH2CF3 E (20 mol%)

CH2Cl2, RT16 h n-Pr

CO2CH2CF3

42% yieldd.r. > 20:1

86% ee

n-Pr n-Pr

CO2CH2CF3 E (20 mol%)

CH2Cl2, RT16 h n-Pr

CO2CH2CF3

41% yieldd.r. > 20:1

84% ee

n-Pr n-Pr

CO2Bn E (20 mol%)

CH2Cl2, RT16 h

85% yield86% ee

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

BzO CHO A (10 mol%)

EtNO2, –20 °C48 h

CHOOBz

Bn NH2

·2.6 Tf2NH

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.

OTMSPh NR

PhTMSO Ph

TMSO Ph

OTMSPh

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

C (20 mol%)N,N-diethyacetamide

H2O, CH2Cl2, RT, 24 h

86% yield99% ee

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

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

PhMe, –20 °C, 72 h

86% yield91% ee

OTMSPh

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%

MeO73%

CO2H MeO60%

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.

78% yield

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

K2CO3, DMF140 °C, 1 h

Ring Closures

ox. ad.

ligandexchange

protonabstraction

red. elim.

Ring Closures

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"

–CuX

Ring Closures

PhMe2SiOMs

THF, RT, 20 h

PhMe2Si Bpin

93% yieldd.r. > 99:1

SiX "Cu–B"

–CuX

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

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.

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

LiOMe, (EtO)2MeSiHTHF, 50 °C, 36 h

83% yield99% ee

Ring Closures

LCuXAr

LCuOMe

MeOSiR3

syn-hydrocupration

Ring Closures

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

LiOMe, (EtO)2MeSiHTHF, 50 °C, 36 h

83% yield99% ee

87% yield99% ee

47% yield97% ee

59% yield98% ee

79% yield99% ee

Ring Expansions

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

Ring Expansions

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

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

DCE, –30 °C, 24 h

76% yield91% ee

(xyl)2

85% yield86% ee

89% yield92% ee

99% yield92% ee

97% yield93% ee

95% yield85% ee

99% yield84% ee

Ring Expansions

DCE, –30 °C, 24 h

76% yield91% ee

(xyl)2

85% yield86% ee

89% yield92% ee

99% yield92% ee

97% yield93% ee

95% yield85% ee

99% yield84% ee

Ring Expansions

DCE, –30 °C, 24 h

76% yield91% ee

(xyl)2

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.

Modern Approaches to Cyclobutanes · R2 R1 R3 R4 R4 R1 R2 R3 ring expansion ring opening (X) n R1...

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