Pt(II) Catalyzed Reorganization ofEnynes: What Can You Do With aPlatinum Carbene Intermediate?

Russell SmithDenmark Group Meeting

11-28-2006

Skeletal Reorganization of 1,6 and 1,7-EnynesE

E

cat. PtCl2

toluene, 80 °C

E = CO2Et

E

E3 h, 86 %

Murai, Organometallics, 1996, 15, 901.

E

E

Ph

E

E

Ph

1 h, 97 %

E

ECl

E

ECl

5 h, 70 %

E

E

E

E1 h, 97 %

E

E4 d, 40 %

E

E

Enyne Type “Metathesis” Using Platinum

• Many structural variations and functional groups are tolerated• Even polyunsaturated compounds undergo metathesis process

Fürstner, J. Am. Chem. Soc., 2001, 123, 11863.

Efforts Toward the Synthesis of Streptorubin B

Formation of propargylicester and ketone wasperformed to allow forfurther functionalization

Fürstner, J. Am. Chem. Soc., 1998, 120, 8305

Cyclization of Keto-enyne Using PlatinumChloride

Palladole complex previously used for similar skeletal RAR (Trost)

Fürstner, J. Am. Chem. Soc., 1998, 120, 8305

Interestingly, strong Lewis acids (BF3·Et2O) also promote cyclization

Mechanistic Insight By Scaling-Up a Reaction?

MAJOR79 %

1 %5 %2 %

Provide a mechanism that accounts for each observed product!(think of a common intermediate)

Simple “Wagner-Meerwein” Cationic Process;NOT Metal Catalyzed

Simple “Wagner-Meerwein” Cationic Process;NOT Metal Catalyzed

Fürstner, J. Am. Chem. Soc., 1998, 120, 8305

Another Side Product Leads to A DifferentReaction Pathway

Can this cyclopropanation process be made general?

Fürstner, J. Am. Chem. Soc., 2000, 122, 6785.

Formation of Cyclopropane Derivatives fromHetero-substituted Enynes

Ability for Pt to catalyze two different process of similarsubstrates may indicate a similar reactive intermediate

Fürstner, J. Am. Chem. Soc., 2000, 122, 6785.

Mechanistic Proposal

Deuterium labeling study

Fürstner, J. Am. Chem. Soc., 2001, 123, 11863.

Mechanistic Proposal

Deuterium labeling study

The carbenoid species undergoes 1,2-hydride stabilization faster than insertion

Further Evidence for Cationic IntermediatesMurai

InoueE

E

[Pt(dppe)(PhCN)2](BF4)2

CHCl3, rt

E = CO2Et

E

E

Two different skeletal reorganizations appear to be operative

Labeling Studies Further Suggest Two ReactionPathways

Inoue, Organometallics, 2001, 20, 3704.

Both types of rearrangements can occur

Cross-over Experiment

CC

C C

C

C

C C

OR

CC

The rearrangement of the homoallyl cation canexplain the change in the skeletal RAR

Mechanistic Picture Involving Homoallyl Cations

The substitution of the enyne helps to stabilize thecarbocation intermediates

CC

C

C

E

E

X Pt2+ CC

C

C

E

E

X

Pt+2

C

C

CE

EY

C

Pt+

Y

X

C

CE

E

C

C

Pt+

X

C

CE

E

C

Pt+ X

CY

YA

B

C

CE

E

C C

YPt+X

A

B

C

CE

E

C C

XY

2+PtC

CE

E

C C

XY

2+Pt

Y

Extension to Cycloisomerization of 1,5-Enynes

cat. PtCl2

toluene/CH3CN

80 °C

MeOTBS

Me

Ph

Ph

MeMe

OTBS

66 %

78 %

81 %

73 %

77 %

72 %

Kozmin, J. Am. Chem. Soc., 2006, 128, 9705.

A wide range of terminal, internal,and arene conjugated systemsparticipate in cyclization

Intramolecular Carbocyclization of Allylsilanesand Allylstannanes

Y

E

E

R1 PtCl2

acetone OR MeOH reflux

E

E

R1

R2

R2

PhO2S

PhO2S

Me

94 %

PhO2S

PhO2S62 %

Y = SiMe3 Y = SnBu3

MeO2C

MeO2C

43 %(81 %)*

Y = SnBu3

MeO2C

MeO2C 50 %

Y = SiMe3

CO2Et

Me

PhO2S

PhO2S87 %

Y = SiMe3

Ph

Reaction is regio-complementary with Lewis Acid promoted cyclizationEchavarren, J. Am. Chem. Soc., 2000, 122, 1221.

Intramolecular Carbocyclization of Allylsilanesand Allylstannanes

Y

E

E

R1 PtCl2

acetone OR MeOH

reflux

E

E

R1

R2

R2

Could the use of an external nucleophile be used to trap carbocation?

Alkoxycyclization of Enynes Catalyzed byPlatinum

Z

Z

cat. PtCl2

ROH

Z

Z

OR

Z = SO2Ph, CO2Me R = Me, Et, allyl, H64-88 %

Ph

Z

Z

cat. PtCl2

MeOH

Z

Z

Ph

OMeH

Z

Z

cat. PtCl2

MeOH

Z

Z

Ph

OMeH

Ph

Echavarren, J. Am. Chem. Soc., 2000, 122, 11549.

Reaction is highly stereoselective with concomitant formation of C-Cand C-O bonds

DFT Calculations Indicate a CyclopropylIntermediate

• Terminal alkyne Clies closer to Pt• Electrophilic center isinternal C (polarized)• Pt-C bond of XXVI isrel. short (1.88 Å)

A platinum carbene is a possible intermediateEchavarren, J. Am. Chem. Soc., 2001, 123, 10511.

Mechanism for Alkoxycyclization

Echavarren, J. Am. Chem. Soc., 2000, 122, 11549.

Asymmetric Pt-catalyzed Hydroxycyclization

100 %0 % ee

100 %5 % ee

91 %20 % ee (85 %)*

91 %13 % ee

* When 0.25 equiv of Ag salts were added, then enantioselectivitysignificantly improved

Use of Ag removes chlorine ligands from Pt ->more electrophilic metal center

Michelet, Pur Appl. Chem., 2006, 78, 397.

Intramolecular O->C Shift Reactions ViaCycloisomerization

Fürstner, J. Am. Chem. Soc., 2001, 123, 11863.

Intramolecular O->C Shift Reactions ViaCycloisomerization

Fürstner, J. Am. Chem. Soc., 2001, 123, 11863.

Cross-over experiment indicates that the allyl group istransferred intramolecularly

Phenol Formation from a Pt-carbeneIntermediate?

OO

cat. PtCl2

acetone, refluxO

HO

O

OH

+ 60 %(2.75:1.0)

OO

O

OH

75 %

O HO

OH

+ 70 %(3.4:1.0)

CO2Me

CO2Me

E

E

E

Can you propose a mechanism for the formation of these phenols?

Echavarren, J. Am. Chem. Soc., 2003, 125, 5757.

Problems Using Wet Solvents!

Echavarren, J. Am. Chem. Soc., 2003, 125, 5757.

Possible Reactions of Furans with Alkynes

Only III could be found for an energy minimum for Friedel-Craft reactionEchavarren, J. Am. Chem. Soc., 2003, 125, 5757.

Formation of Oxepins Create Last C-C Bond

Calc show that the formationof 72 is high in energy

TS most likely occurs viaattack of O on carbene C

Echavarren, J. Am. Chem. Soc., 2003, 125, 5757.

Interception of Carbocationic Species by OtherAromatic Systems

OMe

E

E

E = CO2Me

cat. PtCl2

toluene, 80 °C

E

E

OMe

+

E

E

OMe

76 % yield (99:1)

E

E

Me

+

E

E

Me

47 % (96:4)

E

E

66 % (58:42)

Cl

E

E NR

Ruthenium also catalyzes process albeit with lower selectivityMurai, J. Org. Chem., 2000, 65, 4913.

Origin of Selectivity

Murai, J. Org. Chem., 2000, 65, 4913.

CHALLENGEBased on knowledge obtained of Pt-cycloisomerization chemistry,prepare the 8-membered carbocycle

HO

O

O

OH

Tandem Cycloisomerization/Prins-TypeCyclization

Barluenga, ACIIE, 2006, 45, 2091.

Proposed Mechanism

Barluenga, ACIIE, 2006, 45, 2091.

Pérez-Castells. Chem. Eur. J. 2004, 10, 4938.

Soriano, J. Org. Chem, 2004, 69, 8018.

1,5-Enyne Cyclization Mechanism

R1 R3

R2

R4

Pt R1 R3

R2

R4

Pt

R3

R2R1

R4

Pt-

R2R3

Pt

R4

R1Pt-R1

R4

R3R2R1

R4

Pt-

R2

R2

Pt

R1

R4

R3

R2-M R1

R4

R3

R2

Kozmin, J. Am. Chem. Soc., 2006, 128, 9705.

Conclusions• Use of Pt(II) catalysts can serve as a versatile promoter

for of a number of reactions• A common intermediate has been found which is a

cyclopropyl platinum carbene• DFT calculations have been performed for a number of

platinum catalyzed reactions which has supported theplatinum carbene character of these systems

• The highly efficient atom economy of these processesmake them attractive reactions– Including the high diversity in which similar compounds can

be manipulated• These works may help to provide insight into similar

metal-catalyzed systems (e.g. Au, Ru, Rh)