Sequential Five-Component Construction of the Cyclopenta[e]-[1,3]oxazine Skeleton using Stable 2-Azetine Derivatives

Barluenga, J.; Gómez, A.; Santamarĺa, J.; Tomás, M. Angew. Chem. Int. Ed. 2010, 49, 1306–1308.

Stereoselective Gold-Catalyzed Cycloaddition of Functionalized Ketoenynes:Synthesis of (+)-orientalol

Jiménez-Núñez, E.; Molawi, K.; Echavarren, A. M. Chem. Commun. 2009, 7327–7329.

Mike KarneyShort Literature Presentation

Group Meeting 8-13-2010

Profs. José Barluenga and Antonio M. Echavarren

José Barluenga• Ph. D., University of Zaragoza, 1966 (Aranda)

-Synthesis of diimines and dihydropyrimidines-Aluminum and mercury mediated reactions

• Post-doc, Max Planck Institute, 1967-1970 (Hoberg)-Aluminum mediated additions

• Institute of Organic Chemistry, Spanish Research Council 1970-1972• Associate Professor, University of Zaragoza, 1972-1975• Professor, University of Oviedo, 1975-present

Antonio M. Echavarren• Ph. D., Universidad Autónoma de Madrid (UAM) , 1982 (Fariña)

-Diels-Alder reactions of polycyclic hydroxyquinones• Post-doc, Boston College, 1982-1984(?) (Kelly)

-Synthesis of berinamycinic acid-Synthesis of rifamycin chromophore

• Assistant Prof, UAM, 1984-1986• NATO-fellow, Colorado State University, 1986-1988 (Stille)

-Stille-carbonylative cross-coupling-Stille-Kelly coupling

• Institute of Organic Chemistry, Spanish Research Council 1988-1992• Professor, UAM, 1992-2004• Group Leader, Institute of Chemical Research of Catalonia 2004-present

N

N

S

HOOCOH

CO2

berninamycinic acid

OO

OOHMe NH2

OMeHO

rifamycin chromophore

Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988–4035Ji, J. et al. Pure Appl. Chem., 2005, 77, 2041–2045Carreira, E. et al. J. Med. Chem. 2005, 48, 6035-6053Jung, M. E.; Choi, Y. M. J. Org. Chem. 1991, 56, 6729–6730

2-azetidinone (β-lactam)

NHO

NH NH

Four-membered Nitrogen Heterocycles: Azetidinones, Azetidines, and Azetines

azetidine 2-azetine

• Also possess known medicinal applications

-neuronal receptor antagonists-cholesterol uptake inhibitors

• No documented medicinal applications• Sought after motifs for medicinal applications

-antibiotics (Amoxicillin, Ampicillin, Methicillin, Penicillin, etc)

-cholesterol uptake inhibitors

• Numerous synthetic approaches-Enolate-imine condensations-Isocyanate cycloadditions-Kinugasa Reaction-Staudinger Ketene Cycloaddition

• Stable heterocycles • Stable heterocycles

• Numerous synthetic approaches-Cycloadditions-Ring rearrangements-Reduction of 2-azetidinones-Cyclizations with amine nucleophiles

R1

R2

XNHR3

N

R1R2

R3

• Highly unstable heterocycles-Often undergo spontaneous electrocyclic ring openings

• Few stable forms exist-Require EWG on nitrogen

• Only accessible through multi-step synthesis-No general procedure exists

OCl

N

Me

O6-steps

As a result, azetine chemistry is not well understood

N

R2R1

O•

R4 R5

NOR3 R3

R2R1 R5

R4

Barluengaʼs Solution to Azetine Stabilization

Barluenga, J. et al. Angew. Chem. Int. Ed. 2007, 46, 2610–2612Barluenga, J. et al Angew. Chem. Int. Ed. 2008, 47, 6225–6228Barluenga, J.; Gómez, A.; Santamara, J.; Tomás, M. J. Am. Chem. Soc. 2009, 131, 14628–14629.

NEWG N

R

[M]R1

Fischer-type Metal Carbene Complexes• Electrophilic, low oxidation state metals provide stabilization to electron rich azetine ring (Cr, W, etc.)• Previously established non-heteroatom stable alkynylcarbene complexes, applications to synthesis

45% yield>99% ee

(CO)5MR1

R2

KOtBu

–80 ! 25 °C

R2

R2

R1

R1

73-95% yield

• Use of alkoxy/alkynyl carbene complexes in novel heterocycle formation

Me NPr

(CO)5WOR*

PhNPhPr

H

O Me

(CO)5MR1

R2

THF, –80 ! 25 °C

OH

NR3

OR2

R1

NHR3

51-83% yield

Azetinylcarbene Synthesis

Barluenga, J.; Gómez, A.; Santamarĺa, J.; Tomás, M. Angew. Chem. Int. Ed. 2010, 49, 1306–1308.

NPh

Ph

Bu

(CO)5CrPh

NPh

Fc

Bu

(CO)5CrPh

Np-tol

Ph

Bu

(CO)5CrPh

N

Fc

Bu

(CO)5CrPh

O NPh

Ph

Bu

(CO)5Cr

Ph

NPh

Ph

Bu

(CO)5Cr

Fc

NPh

Ph

Bu

(CO)5WPh

NPh

Fc

Bu

(CO)5WPh

N

Ph

Bu

(CO)5WPh

62% yield 75% yield 56% yield

64% yield 50% yield 72% yield

FeFc =

74% yield 73% yield 63% yield

THF, –80 °C(CO)5M

R1

OMe1. R2 Li

2. TMSOTf, –80 (CO)5MR1

R2 N

H R3

Bu

THF, –80 °C ! 0 °C

NR3

R2

Bu

(CO)5MR1

“Hawaii Five-Oxazine”

Barluenga, J.; Gómez, A.; Santamarĺa, J.; Tomás, M. Angew. Chem. Int. Ed. 2010, 49, 1306–1308.

Proposed Mechanism

9 examples; 32-78% yield

NR3

R2

Bu

(CO)5CrR1

R4 R5

CH3CN, 80 °CO

N

R1

R5

R4

R2

R3

Bu

NR2

R3

Bu

(CO)5CrR1

NR2

R3

Bu

R1

R5

R4

Cr(CO)4

R4 R5

–CON

R2

Bu

R3

R5

R4 • O

R1

Cr(CO)n

CO insertion NR2 Bu

R3O

R1

R5

R4

O

R1

R5

R4

N

R2Bu

R3

4! electrocyclic ringopening

O

N

R1

R5

R4

R2

R3

Bu

Summary and Conclusions

Barluenga, J.; Gómez, A.; Santamarĺa, J.; Tomás, M. Angew. Chem. Int. Ed. 2010, 49, 1306–1308.

(CO)5CrR1

R2

NR3

R2

Bu

(CO)5CrR1

O

N

R1

R5

R4

R2

R3

BuNBu

R3

H

R4 R5

CO (from complex)

• First general procedure to access stable, substituted 2-azetine derivatives• 2-step regioselective route to densely functionalized oxazines• Possible applications as an intermediate in nitrogen containing polycyclic arrays• Catchy tag-line

Gold-Catalyzed Cycloadditions of Enynes

Jiménez-Núñez, E.; Claverie, C. K.; Nieto-Oberhuber, C.; Echavarren, A. M. Angew. Chem., Int. Ed., 2006, 45, 5452–5455.

• Cyclizations allowed one-step synthesis of tricyclic skeletons-allowed access to variety of small natural products (orientalol F, pubineroid B, englerin A, etc)

MeMe

Me

Me

O

H

HO

Me

Me

MeMe

H

O

HO

Me

Me

Me

Me

H O

O

OH

O

HO

O

Ph

orientalol F pubineroid B englerin A

• Proposed mechanism proceeds through carbonyl initiated cyclopropyl ring opening followed by Prins cyclization• Procedure requires minor modification and optimization for specific natural product applications

R

O

Me

Z[Au]

CH2Cl2, 23 °C5-30 min

ZH

R

O

MeZ

H

R

O

Me

RZ O

Me

up to 84% yieldZ = C(CO2Me)2, NTsR = H, Me, i-Pr

Gold-Catalyzed Cycloaddition of Propargyl Ethers

Jiménez-Núñez, E.; Raducan, M.; Lauterbach, T.; Molawi, K.; Solorio, C. R.; Echavarren, A. M. Angew. Chem., Int. Ed., 2009, 48, 6152–6155Jiménez-Núñez, E.; Molawi, K.; Echavarren, A. M. Chem. Commun. 2009, 7327–7329

Me

OMe

Me

Me

RO [Au]

Me

Me

MeMe

H

O

RO

• Propargylic alcohol posed new synthetic challenges for gold-catalyzed methodology-High propensity to undergo Meyer-Schuster rearrangements and possibility of competing 1,5-migration of OR group

Me

Me

Me

Me

RO AuL+

R = H, alkyl, silyl, Ac

Me

HMe OR

HH

MeMe

Me

Me

Me

Me

TESO O 3 mol% A

CH2Cl2, 4 Å MS 23 °C

Me

Me

MeMe

H

O

TESO

65% yieldAu

NN ArAr

NCPh

A: Ar = 2,6-(iPr)2C6H3

10 Steps...One Slide

Jiménez-Núñez, E.; Molawi, K.; Echavarren, A. M. Chem. Commun. 2009, 7327–7329

MeMe

Me

Me

O

H

HO

orientalol F

OH

Me

MeO

Me

Me

1. TBHP, Ti(OiPr)4 L-(+)-DET

2. CCl4, PPh3

92 % over 2 steps

Cl

Me

MeO

Me

Me

OH n-BuLi (5 equiv)

95 %Me

O

Me

Me

Me

HO

Me

Me

TESO

Me

MeO

1. NaBH3CN BF3•OEt2

2. DMP3. TESOTf

61 % over 3 steps

3 mol% A

CH2Cl2, rt

65 %

Me

Me

Me

O

H

MeTESO1. TBAF

2. CrO3•py2

74 % over 2 steps

Me

Me

Me

O

H

Me OHO

10 steps19% overall yieldFirst synthesis of orientalol F

MeMe

Me

Me

O

H

HO

WCl6, n-BuLi

(+)-orientalol F

73 %