1[3 + 3] Cycloaddition by 1,3-Dipoles~ new method for cyclization reaction ~2015. 2. 21.
Nagashima Nozomu

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1. Introduction

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1. introduction

Six membered ring in natural products

 Many natural products contain six-membered rings.
 Formation of six-membered rings would be a key step in synthesis.

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1. introduction

Diels Alder Reaction

R. B. Woodward et al. J. Am. Chem. Soc. 1952, 74, 4223.

K. C. Nicolaou et al. J. Org. Chem. 1985, 50, 1440.

 Diels-Alder reaction is one of certificated methods for six membered ring.

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1. introduction

New method for synthesis of 6 membered ring Feature of [3 + 3] dipole cycloaddition
1. Some substrates would be more suitable for [3 + 3] cycloaddition
2. Quaternary carbon could be introduced before cyclization.
3. Stepwise reaction.

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1. introduction

How to make 1,3-dipole?
Normal molecule: negative charge and positive charge
emerges alternately.
1. Contain hetero atoms at center

2. Molecule changes acceptor to donor stepwise. (or donor to acceptor)

How to make 3-carbon unit dipoles?

71. introduction

Reactive dipole and Stable dipole (1) These dipoles are stable dipoles and the reaction between stabledipoles wouldn’t proceed.
 Stable dipoles react with “Reactive dipoles”

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1. introduction

Reactive dipole and Stable dipole (2) First covalent bond formation step is important and second
cyclization step would be supported by entropic effect.
 The reactive dipole is catalytically formed in the reaction.

How to make the “reactive dipole”?

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2. Three carbon unit 1,3-dipole(2-1) Normal 1,3-dipole species● Trimethylenemethane(2-2) Stepwise1,3-dipole species● NHC conjugated unsaturated aldehyde● Phosphine conjugated allene● Vinylcarbene

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2. Three carbon unit 1,3-dipole

Nature of TMM (1) Dimerization of TMM isproceeded from triplet TMM.
(CIDNP analysis) [3 + 3] cycloaddition would be
difficult by using triplet TMM

How prevent the ring closing and stabilize the ring open state of singlet TMM?

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2. Three carbon unit 1,3-dipole

Nature of TMM (2)Barry M. Trost et. al. JACS, 1979, 101, 6429.

 Cation is stabilized by palladium and prevents ring closing.
 Nucleophilic / Basic character of TMM

Pd-TMM complex reacts with only electron-deficient alkene. (Nucleophilic character)

Pd-TMM complex acts as base. (Basic character)

JACS, 1980, 102, 6359.

122. Three carbon unit 1,3-dipole

Nature of TMM (2)B. M. Trost et. al. JACS, 1979, 101, 6429.

 Cation is stabilized by palladium and prevents ring closing.
 Nucleophilic / Basic character of TMM

Pd-TMM complex reacts with only electron-deficient alkene. (Nucleophilic character)

Pd-TMM complex acts as base. (Basic character)JACS, 1980, 102, 6359.

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2. Three carbon unit 1,3-dipole

Pd-TMM [3 + 3] cycloaddition

Joseph P. A. Harrity et al. JOC, 2003, 68, 4286.

 Reaction between TMM and dipole equivalent was reported.

 TMM also reacts with azomethine imine.
T. Hayashi et. al. JACS, 2006, 128, 6330.

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2. Three carbon unit 1,3-dipole

TMM problems

Controlling substituent position would be difficult.
→ The synthesis is limited to cycloaddition from simple trimethylenemethane.

 Acethoxy group also attacks as nucleophile.
Joseph P. A. Harrity et al. JOC, 2005, 70, 207.

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2. Three carbon unit 1,3-dipole

Sluggish reaction of TMM [3 + 3] cyclization

 Cycloaddition with aziridines which doesn’t have arylsulfoneamide didn’t
proceed.
 This reaction is sluggish reaction.
Joseph P. A. Harrity et al. JOC, 2003, 68, 4286.

Reaction is limited to less-hindered dipoles which have some reactivity?

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2. Three carbon unit 1,3-dipole

Stable TMM dipole

 TMM is used as stable dipole and cyclopropane is used as reactive dipole

M. A. Kerr et al. Org. Lett, 2009, 11, 2081.17
2. Three carbon unit 1,3-dipole

Other TMM (Nakamura TMM)

 Acetal substituent promotes ring cleavage.
 The reactivity of TMM doesn’t decrease.
[3 + 2] cycloaddition by Nakamura TMM
 This TMM is suitable for [3 + 2]
cycloaddition
 This five-membered productwould lead to carboxylic acid inacidic condition.

E. Nakamura. et al. Acc. Chem. Res. 2002, 35, 867.

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2. Three carbon unit 1,3-dipole[3 + 3] cycloaddition by Nakamura TMM

 [3 + 3] cycloaddition with 1,3-dipole is not reported (doesn’t proceed?) 6-membered ring is cleaved in acidic condition.
 Nakamura TMM is not useful for [3 + 3] dipole cycloaddition today.

E. Nakamura et al. Synlett, 2001, 1030-1033.

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Nature of enal with NHC

2. Three carbon unit 1,3-dipole

 NHC conjugated unsaturated aldehyde

F. Glorius et al. ACIE, 2004, 43, 6205.

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NHC catalyzed [3 + 3] cycloaddition

2. Three carbon unit 1,3-dipole

Stereoselectivity of cyclization

K. A. Scheidt et al. JACS, 2007, 129, 5334.

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NHC application with Lewis acid

2. Three carbon unit 1,3-dipole

K. A. Scheidt et al. Nature. Chem. 2010, 2, 766.
K. A. Scheidt et al. Chem. Sci. 2012, 3, 53.

Can this mechanism apply for [3 + 3] cycloaddition??

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NHC problems

2. Three carbon unit 1,3-dipole

 Possibility of dimerization

K. A. Scheidt et al. JACS, 2010, 132, 5345.

 Dimerization between NHC conjugated aldehyde and not conjugatedaldehyde would occur.
 Aldehyde is also activated by Lewis Acid.
→ The reaction is limited to the stable dipole which is more reactive thanstarting a,b-unsaturated aldehydes Lacking certifiable examples
 Cycloaddition partner is limited to azomethine imine. (Only 1 example)→ Reactivity is low and other dipoles can’t react with this dipole?

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Phosphine catalyzed [4 + 2] cycloaddition

2. Three carbon unit 1,3-dipole

O. Kwon et al. JACS, 2003, 125, 4716.

O. Kwon et al. JACS, 2007, 129, 12632.

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Phosphine catalyzed [3 + 3] cyclization

2. Three carbon unit 1,3-dipole

O. Kwon et al. JACS, 2011, 133, 13337.

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Reaction Mechanism

2. Three carbon unit 1,3-dipole Proton transfer (A to D) is promoted by PBu3.
 6-endo cyclization of E is less efficient and proton transfer (E to G) proceeds
when PBu3 is catalyst.
 Control other cyclizations and promote only [3 + 3] cycloaddition is difficult.
 e.e. or d.r. is not discussed in this paper ……
O. Kwon et al. JACS, 2011, 133, 13337.

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Phosphine catalyzed cyclization problems

2. Three carbon unit 1,3-dipole

 5 membered ring formation

P-O interaction would be weaker when R = Bu because of steric hindrance.
 7 membered ring formation

 Steric hindrance of Bu substituents
prevents the 6 membered cyclization

It is difficult to prevent other cyclizations.

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Nature of vinylcarbene

2. Three carbon unit 1,3-dipole

 Vinyl-gold-carbene

F. D. Toste et al. JACS, 131, 11654.

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Vinylrhodiumcarbene

2. Three carbon unit 1,3-dipole

M. P. Doyle et. al. JACS, 2011, 133, 16402

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Effect of Substituents

2. Three carbon unit 1,3-dipole

 TBSO- substituent is important incycloaddition of vinylcarbene.

M. P. Doyle et. al. Angew. Chem. Int. Ed. 2012, 51, 5907

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Combination with Lewis acid

2. Three carbon unit 1,3-dipole

M. P. Doyle et. al. Angew. Chem. Int. Ed. 2012, 51, 9829

 Reaction does not proceed without activation of hydrazone.

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2. Three carbon unit 1,3-dipole

Dearomatization [3 + 3] cycloaddition by vinylcarbene

M. P. Doyle et. al. ACIE, 2013, 52, 12664

M. P. Doyle et. al. JACS, 2013, 135, 12439

What promotes side reaction?

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2. Three carbon unit 1,3-dipole

Reaction mechanism (1)1. Lewis acidic dirhodium compound promotes[3 + 2] cycloaddition (Entry 2, 4, 10)
2. Lewis base additives promotes [3 + 2]
3. Cyclopropene was also demonstrated to bea precursor of the same metal carbene
intermediate (Entry 11 to 15)

M. P. Doyle et. al. JACS, 2013, 135, 12439

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Reaction mechanism (2)2. Three carbon unit 1,3-dipole• Stable dipoles which were not sufficiently basic don’t cause inhibition ofdirhodium catalysts toward metal carbene formation.
• Dirhodium compounds are mild Lewis acids that coordinate with Lewisbases (Isoquinolinium/ pyridinium methylylides are readily accessiblenucleophiles) .

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Vinylcarbene reactivity
 Gold catalyst

 Rhodium catalyst

2. Three carbon unit 1,3-dipole

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3. Summary

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1,3-dipole cycloaddition methods

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Comparison of 1,3-dipole cycloaddition methods

3. Summary

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Future of [3 + 3] cycloaddition

3. Summary Possibility of high stereoselectivity or enantioselectivity
 Stereoselectivity or enantioselectivity is controlled by chiral auxiliary.
→ Selectivity will be more strengthened by 2 chiral auxiliary??

 First addition step could be reversible?

If first step is reversible, compounds attacked from concave side are
obtained selectively?