The [3+2] Cycloaddition Reaction

OO

OMeMe

OPMB

XX

OTBSLecture Notes

Key Reviews:

AsymmetricK. V. Gothelf, K. A. Jorgensen, Chem. Rev. 1998, 98, 863.

NitronesP. N. Confalone, Org. React. 1988, 36, 1.

Azomethine YlidesI. Coldhaim, R. Hufton, Chem. Rev. 2005, 105, 2765.

[3+2] Dipolar Cycloadditions: A Reaction You Have Seen Before

ABC

Dipolarcycloaddition

E DC

BA

E D or[3+2] reaction

OO O

OO

O

R1 R2Dipolar

cycloaddition O

R1O O

R2

OO

OR1

R2

Me2Sor PPh3

in situreduction

Dipolarcycloreversion

O O

R2R1+

+

Criegeezwitterion

R1 R2

[3+2] Dipolar Cycloadditions: General Reaction and Classes of 1,3-Dipoles

ABC

R N O

XNY

N N NR

nitrile oxides

azomethine ylides

nitrones azides

diazoalkanes carbonyl ylides

Dipolarcycloaddition

E DC

BA

E D

X = electron withdrawing groupY = electron donating group

RO R4R1

R3R2

NO

R1

R3

R2

N NR1

R2

or[3+2] reaction

[3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity

NO

+EWG

EWG = CO2Et, NO2

EWG= N

Regioselectivity

OEWG

NO

+EDG

EDG = OMe, alkyl, Ph

EDG= N

OEDG

[3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity

NO

+EWG

EWG = CO2Et, NO2

EWG= N

Regioselectivity

OEWG

NO

+EDG

EDG = OMe, alkyl, Ph

EDG= N

OEDG

Note:azides do not follow

this trend

Reactivity:R1

R2

R1

R2

>

[3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity

NO

+EWG

EWG = CO2Et, NO2

EWG= N

Regioselectivity

OEWG

NO

+EDG

EDG = OMe, alkyl, Ph

EDG= N

OEDG

Note:azides do not follow

this trend

Diastereoselectivity

O N OR1

O NOR1

endotransition state exo

transition state

Reactivity:R1

R2

R1

R2

>

N OO

ORR2O

R2O

R1

+O

N R1

OOR2

ON R1

OOR2

Nitrile Oxides: Synthesis

R O

H HONH2•HClR N

HOH

NaOX

R N

XOHR N O

nitrile oxide

-[HX]

X = Cl, Br, I

R NO2

R N C O

R N O

The isocyanate is serving as a dehydrating reagent; can you rationalize a mechanism?

nitrile oxide

Nitrile Oxides: Synthesis

R O

H HONH2•HClR N

HOH

NaOX

R N

XOHR N O

nitrile oxide

-[HX]

X = Cl, Br, I

R NO2

R N C O

R N O

The isocyanate is serving as a dehydrating reagent; can you rationalize a mechanism?

nitrile oxide

Nitrile Oxides: Applications in Total Synthesis

OTBDPS

ON

Me

OTBDPS

Me

NOH N

O

OTBDPS

Me

Nitrile oxide1,3-dipolar

cycloadditionaq. NaOCl,CH2Cl2, 25 °C (59%)

H H

OTESOTMS

Me

OTBDPSMeO2C

O

OTBDPS

Me

OH

Zn, AcOH,25 °C, 4 h (66%)

MeON

N

MeH

HMe

OAc

CO2MeOH

NH

N

H

MeO2C

OH

Me

vinblastine

T. Fukuyama and co-workers, J. Am. Chem. Soc. 1999, 121, 3791For a review, see Classics in Total Synthesis II, Chapter 18

Nitrile Oxides: Applications in Total Synthesis

Nitrile oxide1,3-dipolar

cycloaddition(89%)

R.V. Stevens, J. Am. Chem. Soc. 1975, 97, 5940.

MeO2C NO2

Me Me

PhNCOMeO2C

Me Me

N O

ON

MeMe

O O

Me Me

MeO2C

Benzene, 25 °C

ON

MeMe

Me Me

MeO2CNO

O

OMe Me

ON

MeMe

Me Me

MeO2C

ON

MeMe

O

O

A

A

ANitrile oxide1,3-dipolar

cycloaddition

Nitrile Oxides: Applications in Total Synthesis

R.V. Stevens, J. Am. Chem. Soc. 1975, 97, 5940.

O

Me Me

ON

MeMe

Me Me

MeO2C

ON

MeMe

O

O

ON

MeMe

Me Me

MeO2C

ON

MeMeNO

ON

MeMe

Me Me

MeO2C

ON

MeMe

Me

O NMeO

MeMe

octamethylcorphin

Nitrile oxide1,3-dipolarcycloaddition

B

B

N N

NN

MeMe

Me Me

MeMe

Me Me

Nitrile Oxides: Applications in Total Synthesis

R.V. Stevens, J. Am. Chem. Soc. 1975, 97, 5940.

ON

MeMe

Me Me

MeO2C

ON

MeMeO NMeO

MeMe

N N

NN

MeMe

Me Me

MeMe

Me Me

octamethylcorphin

ONH2

MeMe

Me Me

MeO2C

OH2N

MeMeOH2NMeO

MeMe

H2, Raney NiMeOH, pH 7

NHO

N

NCOMe

OMeMe

Me Me

MeMe

Me Me

Et3N, CHCl3,25 °C, 24 h Imine formation

Nitrile Oxides: Applications in Total Synthesis

P. N. Confalone, J. Am. Chem. Soc. 1980, 102, 1954.

NaSOAc

NO2

HS

NO2+

-[HOAc]

S

O2N

S

NO

S

ON

H

H

H

S

HO

H

HH2N

H

S HHO2C

NHHN

O

biotin

Michaeladdition

Intramolecularnitrile oxide1,3-dipolar

cycloaddition

LiAlH4

PhNCO

+

Nitrile Oxides: Applications in Total Synthesis

P. N. Confalone, J. Heterocyclic Chem. 1990, 31.

Intramolecular nitrile oxide1,3-dipolar cycloaddition

N

NO2

OMeN

N

OMe

Cl N C O

Et3N, toluene,80 °C

O

NOMe

NO

19-membered ring[masked aldol product]

(82%)

For reviews:A. Padwa, Angew. Chem. Int. Ed. Engl. 1976, 15, 123

W. Oppolzer, Angew. Chem. Int. Ed. Engl. 1977, 16, 10.

Nitrones: Preparative Methods

NO

NOH

R1 R2 R1 R2

nitrone

NHOH

R1 R2O+HgO

Oximeoxidation

Nitrones: Applications in Total Synthesis

J. Tufariello, Acc. Chem. Res. 1979, 12, 396.

NO

CO2Me

OHNitrone

1,3-dipolarcycloaddition

N O

CO2Me

OH

H

48 kcal

+

Nitrones: Applications in Total Synthesis

J. Tufariello, Acc. Chem. Res. 1979, 12, 396.

NO

CO2Me

OHNitrone

1,3-dipolarcycloaddition

N O

CO2Me

OH

H

48 kcal

NH

CO2MeH

OMs

OHN

HOH

supinidine

1. cyclize2. dehydrate3. LiAlH4

1. MsCl2. H2, heat

+

Nitrones: Applications in Total Synthesis

J. Tufariello, Acc. Chem. Res. 1979, 12, 396.

NO Nitrone

1,3-dipolarcycloaddition

N O

N

CO2MeCO2Me N O

CO2Me

O

O O

H H

O

CO2MeOH

NCO2Me

OHO

CO2MeNCO2Me

O1. MsCl, py

2. DBU

DBU = Cl

mCPBA

Oxidativeringopening

Nitrone1,3-dipolar

cycloaddition[protection step]

N

N

MeO2CMeO2C

H

Nitrones: Applications in Total Synthesis

J. Tufariello, J. Am. Chem. Soc. 1978, 100, 3638.J. Tufariello, J. Am. Chem. Soc. 1979, 101, 2435.

NCO2Me

O

Nitrone [3+2]cycloaddition

xylene, Δ

[3+2] cycloreversionN O

CO2Me

NMe CO2Me

O

O

Ph

cocaine

N O CO2Me

NO CO2Me

1. MeI2. H2

3. BzCl

(66% overall)

MeO2C

H H

Nitrones: Applications in Total Synthesis

W. Oppolzer, M. Petrzilka, J. Am. Chem. Soc. 1976, 98, 6722.W. Oppolzer, M. Petrzilka, Helv. Chim. Acta 1978, 61.

Nitrone[3+2]

cycloaddition

O

Me+

O

Me

H

H

N

Me

H

H

OHHN

Me

H

H

OH

NO MeN

MeO

H H

HHH

NMe

H

H

Me

HOH

NMe

H

H

Me

O

CrO3

LiAlH4

MeO SO

OF

(67%)Diels-Alder

reaction

SnCl4 H2NOH•HCl NaBH3CN(98%

overall)

O

(94%overall)

H

H

luciduline

Nitrones: Applications in Total Synthesis

E. G. Baggiolini and co-workers, J. Org. Chem. 1986, 51, 3098.

Nitrone[3+2]

cycloaddition

MeMe Me

MeOH

Me

OHHO

H

1α,25-dihydroxyergocalciferol

MeMe N

Me

HHO

O MeO2CMe

Me MeMe Me

MeO

CO2Me

H

NMe

endo product

MeMe Me

MeHO

Me

H

NMe Me

MeMe Me

MeHO

Me

H

MeMe Me

MeO

Me

H

NMe

3 steps

MeI, toluene,60 °C; Zn dust,

AcOH

xylene, 140 °C

MeI;t-BuOK

Hofmanndegradation

HO HO

HOHO

Nitrones: Applications in Total Synthesis

P. L. Fuchs and co-workers, J. Am. Chem. Soc. 2006, 128, ASAP.D. L. Hughes and co-workers, J. Org. Chem. 2004, 69, 1598.

Intramolecularnitrone [3+2]cycloaddition

MgBr1.

2. PCC, CH2Cl2

O

EtO HO

CN

CN

N

CN

CN

HON

CN

CN

HON

CN

CN

O

O CN

Michael addition

1,3-protonshift

H2NOH•HCl, NaOAc,MeOH/MeCN, 50 °C

RuCl

ClNN

Me

MeMe

Me

Me

Me

Oi-PrA

A,

Olefin cross-metathesis

(62%)(91% overall)

Nitrones: Applications in Total Synthesis

P. L. Fuchs and co-workers, J. Am. Chem. Soc. 2006, 128, ASAP.D. L. Hughes and co-workers, J. Org. Chem. 2004, 69, 1598.

Intramolecularnitrone [3+2]cycloadditionN

CN

CN

O

N

CN

CN

ON

CN

CN

OHNHO

histrionicotoxin

N

CN

O

NC

N

CN

ONC

H

thermodynamicproduct

Intramolecularnitrone [3+2]cycloaddition

Retro [3+2]cycloaddition

kinetic product

toluene, 180 °Csealed tube

(95%)

(89% overall)

For original concept, see:R. Grigg, J. Chem. Soc., Perkin Trans. 1 1984, 47

Carbonyl Ylides (Oxidopyryliums): Using Cyclic Systems

O

O

AcO O

O

AcO O

O

O

OR2

O

O

O

R2

R1

R2R1

OR1

1,3-Dipolarcycloaddition

exo adduct

Base -[ OAc]

H

H

In cyclizations of this type, the ENDO isomer places the substituents on the dipolarophile anti to the oxido bridge. Accordingly, the EXO isomer is the one in which

these substituents are syn to the resultant oxygen bridge.

Carbonyl Ylides (Oxidopyryliums): Using Cyclic Systems

Me

O

MeH

OH

H

Me

MeH

OHHO

OH

phorbol

O

MeO

OTBS

OAc

OTBS

Me

OH

AcO

O

O

O

HMe

OAc

AcO

TBSO DBU,CH2Cl2, 25 °C

exo adduct

Oxidopyryliumformation

1,3-Dipolarcycloaddition (92%)

MeO

OOTBS

OAc

11

8

OH

11

8

P.A. Wender and co-workers, J. Am. Chem. Soc. 1989, 111, 8954 and 8957.

Carbonyl Ylides (Oxidopyryliums): Using Cyclic Systems

P.A. Wender and co-workers, J. Am. Chem. Soc. 1997, 119, 12976.For a review, see: Classics in Total Synthesis II, Chapter 6

OO

OAc

OTBS

Me

OAc

OBn

O

Me OAc

OBn

O

OTBS

OO

OTBS

Me

OAc

OBn

OTBS

Me

OH

O

exo adduct

OAc

OBn

DBU,CH3CN,

(84%)1,3-Dipolarcycloaddition

80 °C, 1 h

MeO

OOTBS

OBn

OAc

OMe

O

O

OOH

OMe

Me

MeH

OH

O

O

H

resiniferitoxin

Carbonyl Ylides (Oxidopyryliums): How to Make Precursors

P.A. Wender and co-workers, J. Am. Chem. Soc. 1997, 119, 12976.For a review, see: Classics in Total Synthesis II, Chapter 6

OO

OH

OTBS

Me

OAc

OBn

OH

Me

OAc

OBn

OOTBS

OOH

Me

OAc

OBn

OOTBS

OH

O

Me

OAc

OBn

OOH

OTBS

Ketalization(100%)

-[H ]

OH

Me

OAc

OBn

OOTBS

mCPBA,THF,

0→25 °C,12 h

Note: Although the free hydroxylcontrols the addition of oxygen to

the indicated bond of the furan,had addition to the other olefin occurred, the same butenolideproduct would have resulted

(i.e. degenerate mechanistic pathways)

Carbonyl Ylides (Oxidopyryliums): Applications in Total Synthesis

D.L. Boger and co-workers, J. Am. Chem. Soc. 2006, 128, 10597.D.L. Boger and co-workers, J. Am. Chem. Soc. 2006, 128, 10589.

MeONMe

NH2MeO

NMe

NH

OHNHN O

CO2Me

MeONMe

NH

NNO

CO2Me

MeONMe

N

NNO

CO2Me

O

BnO

EtO

OBn

Et

OH

H2N NH

O

CO2Me

O

NN

1.

2.

AcOH, THF

TsCl,Et3N

Robinson-GabrielCyclo-dehydration

EDC, 4-DMAP(78% overall)

(74% overall)

Carbonyl Ylides (Oxidopyryliums): Applications in Total Synthesis

D.L. Boger and co-workers, J. Am. Chem. Soc. 2006, 128, 10597.D.L. Boger and co-workers, J. Am. Chem. Soc. 2006, 128, 10589.

MeONMe

N

NNO

CO2Me

O

BnO

EtMeO

NMe

N

O

NN

O EtOBn

CO2Me

MeONMe

N

O

EtO

CO2MeOBn

MeON

N

MeH

H

EtOAc

CO2MeOH

(−)-vindoline

MeON

N

MeH

EtOBn

CO2Me

O

O

(53% overall)

Concurrently forms:4 C-C bonds

6 stereocenters (4 quaternary)3 rings

HeteroDiels-Alder

reaction

RetroDiels-Alderreaction

[-N2]

[3+2]cycloaddition

TIPB,230 °C

Azomethine Ylides: Formation

For a review, see: I. Coldham, R. Hufton, Chem. Rev. 2005, 105, 2765.

azomethine ylideElectrocyclicring-opening

NR

R2R1NR

R1 R2

R1 OHNR

R2+

R1 N

O CO2H

R2R

-[H2O]

NR

R2R1Base

Azomethine Ylides: Huisgen's Pyrrole Synthesis

N

O CO2H O

N

O

[3+2]cycloaddition

O

O

NN

-[CO2]

RetroDiels-Alder

reaction

-[H2O]

Azomethine Ylides: Applications in Total Synthesis

N

O CO2H

CO2MeMeO2C[3+2]

cycloaddition -[CO2]

RetroDiels-Alderreaction

-[H2O]

J. Rebek, Tetrahedron Lett. 1977, 3027.

Me

MeO2C Ac2O

N

O

Me

MeO2C O O

O Me

Me

MeO2C

N

OO

Me

MeO2C

N

CO2MeMeO2C

N

CO2Me

Me

OMeO2C KH, THFDieckmanncyclization

O

O

MeO

Me N NH

OMe

OCONH2

mitomycin A

Δ

Azomethine Ylides: Applications in Total Synthesis

P. Garner, W.B. Ho, H. Shin, J. Am. Chem. Soc. 1993, 115, 10742.

N

N

HCO2H

Me

OH

quinocarcin

N

O

O

HOMeO

Me

MeN3

toluene,25 °C

(99%)

N

O

O

HOMeO

MeNN

N

Me

N

O

O

HOMeO

Me

N Mehν,

Pyrexdioxane(90%)

hν,quartz

MeON

HOMeO

Me

NO

O

Me

NO2S

OMe Me

Me

N

N

CONX

Me

MeO

O

O

HO

Electrocyclicring-opening

A

A[3+2]

addition

[3+2] addition

exo product

Azides: Regioselectivity and Reactivity

K. B. Sharpless and co-workers, Angew. Chem. Int. Ed. 2002, 41, 2596.K. B. Sharpless and co-workers, J. Am. Chem. Soc. 2005, 127, 210.

R2NNN

R1

Δ NN

N NN

N

R1 R1

R2 R2+ (~1:1)[3+2]

cycloaddition

R2NNN

Azides: Regioselectivity and Reactivity

K. B. Sharpless and co-workers, Angew. Chem. Int. Ed. 2002, 41, 2596.K. B. Sharpless and co-workers, J. Am. Chem. Soc. 2005, 127, 210.

R2NNN

R1

Δ NN

N NN

N

R1 R1

R2 R2+ (~1:1)[3+2]

cycloaddition

R1CuX

R1 CuL

R1 CuLN

NN

R2

R2NNN

NN

N

R1

R2

rt, 12-24 h

only product formed

As you might expect,this selectivity can only

occur with alkynes bearinga terminal hydrogen

R2NNN

Azides: Applications in Total Synthesis

K.D. Bodine, D.Y. Gin, M.S. Gin, J. Am. Chem. Soc. 2004, 126, 1638.

O

OO

O

HO

HO

O HOOOH

OH

HO

O

OO

O

OH

OH

OOH OHO

HO

OH

OH

HO

OH

OHHO

O

O O

O O

BnOO

N

OBn

BnO

OBn

OBnOBn

OBn

BnO

NN

OBn

α-cyclodextrin

HO

O

OO

OH

OHO HOOHO

OH

HO

O

OO

OH

HOOOH OOH

HO

OH

OH

HO

OH

OH

HO

HO

N

NN

N

NN

CuI, DBU;H2, Pd/C

(80%)Tandem

[3+2]cycloaddition

Azides: Applications in Total Synthesis

T. Fukuyama, L. Yang, J. Am. Chem. Soc. 1989, 111, 8303.

OBnMeO

MeOMe

N

OO

SEt

Ph

OTMS

N N

OBnMeO

MeOMe

OO

SEt

Ph

OTMS

NN N

HH

toluene,110 °C,

3 h(86%)[3+2]cyclo-

addition

Azides: Applications in Total Synthesis

T. Fukuyama, L. Yang, J. Am. Chem. Soc. 1989, 111, 8303.

OBnMeO

MeOMe

N

OO

SEt

Ph

OTMS

N N

OBnMeO

MeOMe

OO

SEt

Ph

OTMS

NN N

HH

toluene,110 °C,

3 h(86%)

OBnMeO

MeOMe

OO

SEt

Ph

OTMS

NN

HH

N

[3+2]cyclo-

addition

Azides: Applications in Total Synthesis

T. Fukuyama, L. Yang, J. Am. Chem. Soc. 1989, 111, 8303.

N NH

OMeO

O

H2N

Me

OCONH2

mitomycin C

O

O

MeO

Me

isomitomycin A

N

NHOMe

H

OCONH2NH3,

MeOH

Can yourationalize

a mechanism?

(85%)

OBnMeO

MeOMe

N

OO

SEt

Ph

OTMS

N N

OBnMeO

MeOMe

OO

SEt

Ph

OTMS

NN N

HH

toluene,110 °C,

3 h(86%)

OBnMeO

MeOMe

OO

SEt

Ph

OTMS

NN

HH

N

OBnMeO

MeOMe

OO

SEt

Ph

OTMS

NH

[3+2]cyclo-

addition

[-N2]