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哥伦比亚教授有机化学课件[3+2]Cycloaddition


The [3+2] Cycloaddition Reaction
Lecture Notes

Key Reviews:

Asymmetric K. V. Gothelf, K. A. Jorgensen, Chem. Rev. 1998, 98, 863. Nitrones P. N. Confalone, Org. React. 1988, 36, 1. Azomethine Ylides I. Coldhaim, R. Hufton, Chem. Rev. 2005, 105, 2765.

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

A E

C D

Dipolar cycloaddition or [3+2] reaction

B A C E D

Criegee zwitterion O O O Dipolar cycloaddition O R1 O O R2 Dipolar cycloreversion R1 O O
+

O R2

R1

R2

O
+

O R2

Me2S or PPh3 in situ reduction

R1

O O

O R2

R1

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

A E

C D

Dipolar cycloaddition or [3+2] reaction

B A C E D

R1 R N O R2 R3 N R O N N N

nitrile oxides
R Y N X

nitrones

azides

R1 N N R2

R1 R2

O R3

R4

azomethine ylides

diazoalkanes X = electron withdrawing group Y = electron donating group

carbonyl ylides

[3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity
Regioselectivity EWG N O + = EWG = CO2Et, NO2 EDG N O + = EDG = OMe, alkyl, Ph EDG N O EDG EWG N O EWG

[3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity
Regioselectivity EWG N O + = EWG = CO2Et, NO2 Reactivity: EDG N O + = EDG = OMe, alkyl, Ph EDG N O EDG R1 > R2 R2 R1 EWG N O Note: azides do not follow EWG this trend

[3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity
Regioselectivity EWG N O + = EWG = CO2Et, NO2 Reactivity: EDG N O + = EDG = OMe, alkyl, Ph Diastereoselectivity O R2O O N OR2 O O R1 N O O + R1 OR R2O O O EDG N O EDG R1 > R2 R2 R1 EWG N O Note: azides do not follow EWG this trend

N

R1

R1

N

R1 OR2

endo transition state

O N exo transition state

O

Nitrile Oxides: Synthesis

H R O

HONH2?HCl R

H N OH R NO2

X = Cl, Br, I

NaOX

R N C O

R

N O

-[HX] R

X N OH
R N O

nitrile oxide

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

Nitrile Oxides: Applications in Total Synthesis
O N OH Me N Me

aq. NaOCl, CH2Cl2, 25 ° C

Nitrile oxide 1,3-dipolar cycloaddition (59%)

N O

Me

H
OTBDPS

H
OTBDPS OTBDPS

OH N Me H N H MeO2C MeO N Me H N H Me OAc OH CO2Me MeO2C OTBDPS OTES OTMS Me

Zn, AcOH, (66%) 25 ° 4 h C,
O

Me OH

OTBDPS

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

Nitrile Oxides: Applications in Total Synthesis

MeO2C

NO2

PhNCO Benzene, 25 ° C

MeO2C Me Me

N

O

A Nitrile oxide 1,3-dipolar cycloaddition

Me Me

(89%)

A O O O O O N MeO2C N O Me Me A Nitrile oxide 1,3-dipolar cycloaddition MeO2C N O Me Me Me Me Me Me O N Me Me MeO2C N O

O

O Me Me

Me Me

Me Me

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

Nitrile Oxides: Applications in Total Synthesis
O O O N MeO2C N O Me Me B O Me Me Me Me Me N Me Me Me Me octamethylcorphin Me Me N N N Me Me Me Me O O Me N O N MeO2C N O Me Me Nitrile oxide B 1,3-dipolar cycloaddition Me Me O N MeO2C N O Me Me Me Me O N Me Me

Me Me

Me Me

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

Nitrile Oxides: Applications in Total Synthesis
Me Me O O Me N O N MeO2C N O Me Me Me Me H2, Raney Ni MeOH, pH 7 MeO2C Me Me O O Me H2N O H2N NH2 O Me Me Me Me

Me Me

Me Me

Et3N, CHCl3, Imine formation 25 ° 24 h C, Me Me N Me Me Me Me octamethylcorphin Me Me N N N Me Me Me Me Me Me O O COMe NH N N Me Me

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

Nitrile Oxides: Applications in Total Synthesis

NO2 + OAc NaS

-[HOAc]

NO2
+

O2N HS Michael addition S

PhNCO

O HN NH HO H2N H S H HO2C S H H LiAlH4 S N O H H H Intramolecular nitrile oxide 1,3-dipolar cycloaddition N S O

biotin

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

Nitrile Oxides: Applications in Total Synthesis
Me N O Cl N C O Et3N, toluene, 80 ° C Me N O

NO2

N

O

Intramolecular nitrile oxide (82%) 1,3-dipolar cycloaddition Me N For reviews: A. Padwa, Angew. Chem. Int. Ed. Engl. 1976, 15, 123 W. Oppolzer, Angew. Chem. Int. Ed. Engl. 1977, 16, 10. N 19-membered ring [masked aldol product] P. N. Confalone, J. Heterocyclic Chem. 1990, 31. O O

Nitrones: Preparative Methods

R1

R2 N OH

HgO Oxime oxidation

R1

N O nitrone

R2

R1

NH + O OH

R2

Nitrones: Applications in Total Synthesis

CO2Me N O + OH Nitrone 1,3-dipolar cycloaddition

H

CO2Me

N O 48 kcal

OH

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

Nitrones: Applications in Total Synthesis

CO2Me N O + OH Nitrone 1,3-dipolar cycloaddition

H

CO2Me

N O 48 kcal

OH

1. MsCl 2. H2, heat

H N supinidine

OH

1. cyclize 2. dehydrate 3. LiAlH4

H NH

CO2Me OH OMs

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

Nitrones: Applications in Total Synthesis

N O

CO2Me CO2Me Nitrone 1,3-dipolar cycloaddition N O

mCPBA N O H H O O O

CO2Me

N DBU = N Cl

Oxidative ring opening

N O MeO2C

CO2Me 1. MsCl, py 2. DBU MeO2C

CO2Me N O OH CO2Me Nitrone 1,3-dipolar cycloaddition [protection step] N O OH

CO2Me

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

Nitrones: Applications in Total Synthesis

CO2Me N O MeO2C xylene,?? [3+2] cycloreversion N O CO2Me N

O

CO2Me

Nitrone [3+2] cycloaddition

(66% overall)

Me

CO2Me N O O cocaine Ph

1. MeI 2. H2 3. BzCl

N

O CO2Me H

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

Nitrones: Applications in Total Synthesis
O + SnCl4 Me (67%) Diels-Alder reaction H Me H O H H2NOH?HCl N OH HN H NaBH3CN (98% Me overall) H Me OH

H

H O H O MeO S F O LiAlH4 (94% overall)

Me H N Me H O H luciduline

CrO3 HO

Me H N Me H H

N O H

H Me H Nitrone [3+2] cycloaddition O N

H Me H

H

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

Nitrones: Applications in Total Synthesis
Me Me Me N O MeO2C CO2Me Me Me N O Me

Me Me

Me Me

Me 3 steps Me Me N O Me HO H Me Me

HO

H

xylene, 140 ° C Nitrone H [3+2] HO endo product cycloaddition Me Me Me Me Me OH Me H Me Me HO H

MeI, toluene, 60 ° Zn dust, C; AcOH Me Me Me MeI; t-BuOK Me Me N HO Me Me HO H Me Me

Hofmann degradation

HO OH 1?,25-dihydroxyergocalciferol

HO

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

Nitrones: Applications in Total Synthesis
O EtO H
Me Me N Me Cl N Me

1.

MgBr

A, O CN Olefin crossmetathesis (62%) CN O

CN

2. PCC, CH2Cl2 (91% overall)
Me Me

A

Ru Cl O i-Pr

Intramolecular H2NOH?HCl, NaOAc, nitrone [3+2] MeOH/MeCN, 50 ° cycloaddition C

CN O N 1,3-proton shift CN CN HO N

CN HO Michael addition CN N

CN

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.

Nitrones: Applications in Total Synthesis
CN O N NC CN O CN N Intramolecular nitrone [3+2] cycloaddition (89% overall) NC H kinetic product toluene, 180 ° Retro [3+2] C sealed tube cycloaddition CN Intramolecular nitrone [3+2] cycloaddition (95%) CN thermodynamic product CN O N CN O N

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

HN HO

histrionicotoxin

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.

Carbonyl Ylides (Oxidopyryliums): Using Cyclic Systems

O

O

O

Base
AcO O AcO O

-[ OAc]
O

H O R1 R2 H

1,3-Dipolar O cycloaddition
O R1

O R1 R2 O R2 O

exo adduct

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

O TBSO AcO O
11

OAc

8

DBU, CH2Cl2, 25 ° C Oxidopyrylium formation

O Me

11

OAc
8

O

H

Me

OTBS

1,3-Dipolar cycloaddition
HO Me H OH Me O OH OH OH Me AcO Me H H Me O O OTBS H O Me

(92%)

OAc

O OTBS

phorbol

exo adduct

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

Carbonyl Ylides (Oxidopyryliums): Using Cyclic Systems
OBn Me O O OAc OAc OTBS Me OBn

DBU, CH3CN, 80 ° 1 h C,

O Me O OAc O OBn OTBS OTBS

OAc

O

1,3-Dipolar cycloaddition
Me O Me H O Me O OH O H O O OMe OH Me O O OTBS H O OBn OAc O Me

(84%)

OAc OBn OTBS

exo adduct

resiniferitoxin

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

Carbonyl Ylides (Oxidopyryliums): How to Make Precursors

OBn OTBS Me OAc OH

OBn

OBn

mCPBA, THF, 0?25 ° C, 12 h

OTBS

Me

-[H
OAc OH O

]

OTBS O

Me OAc OH OH

O

O

OBn

OBn Me

Note: Although the free hydroxyl controls the addition of oxygen to the indicated bond of the furan, had addition to the other olefin occurred, the same butenolide product would have resulted (i.e. degenerate mechanistic pathways)

Me O O OAc OH OTBS

Ketalization (100%)

O

OAc OH O OTBS

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

Carbonyl Ylides (Oxidopyryliums): Applications in Total Synthesis
1. NH2 MeO N Me 2. H2N N O N CO2Me H AcOH, THF (74% overall) O N MeO HN N HN Me NH O O CO2Me

TsCl, Et3N Et O N MeO N Me N O N BnO CO2Me Et OBn O OH EDC, 4-DMAP (78% overall) MeO

RobinsonGabriel Cyclodehydration

NH O N Me N N

CO2Me

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.

Carbonyl Ylides (Oxidopyryliums): Applications in Total Synthesis
O N
MeO N Me

O TIPB, 230 ° C
MeO Hetero Diels-Alder reaction N Me

N N O N Et OBn CO2Me

[-N2] Retro Diels-Alder reaction

N O N BnO CO2Me

Et

O
Concurrently forms: 4 C-C bonds 6 stereocenters (4 quaternary) 3 rings

N
MeO N

O
Me

O
N H N

CO2Me

Et OBn

Et
MeO N Me H OAc OH CO2Me MeO N Me

O

Et OBn

[3+2] cycloaddition (53% overall)

(?)-vindoline

H CO Me 2

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.

Azomethine Ylides: Formation
R HN

R1

O

+

R2

R N R1 R2 Electrocyclic ring-opening

R1

R N

R2

Base

R1

R N

R2

azomethine ylide

-[H2O] O R1 N R CO2H R2

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

Azomethine Ylides: Huisgen's Pyrrole Synthesis

O O N CO2H -[H2O] O N

[3+2] cycloaddition O -[CO2] N Retro Diels-Alder reaction O N

Azomethine Ylides: Applications in Total Synthesis
O MeO2C Me O N CO2H Ac2O MeO2C Me O O N O Me ? -[H2O] MeO2C Me O O N

MeO2C

Retro CO2Me Diels-Alder [3+2] reaction cycloaddition -[CO2]

O MeO Me N

OCONH2 OMe NH

MeO2C Me

O CO2Me N KH, THF Dieckmann cyclization MeO2C MeO2C Me N

CO2Me

O mitomycin A

J. Rebek, Tetrahedron Lett. 1977, 3027.

Azomethine Ylides: Applications in Total Synthesis
O HO MeO N MeO MeN3 toluene, 25 ° C [3+2] addition (99%) HO MeO O N N MeO N N Me h?, Pyrex dioxane (90%) O HO MeO N MeO N Me

A O N O2S N H O MeO N H CO2H Me

Me

Me h?, Electrocyclic quartz ring-opening

N HO O N MeO O Me

Me CONX HO MeO O N Me O N Me

A [3+2] addition

quinocarcin

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

Azides: Regioselectivity and Reactivity

N N N R2 R1

N N N R2

? [3+2] cycloaddition

N R1

N

N

R2 +

R2 N N N R1

(~1:1)

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.

Azides: Regioselectivity and Reactivity

N N N R2 R1

N N N R2

? [3+2] cycloaddition

N R1

N

N

R2 +

R2 N N N R1

(~1:1)

R1 As you might expect, this selectivity can only occur with alkynes bearing a terminal hydrogen N N N R2

CuX rt, 12-24 h

R1

CuL

N N N R2

R1 N

R1 only product formed

CuL N N R2

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.

Azides: Applications in Total Synthesis
OBn OBn O O BnO

O BnO

OBn OBn O O BnO

OBn OBn O N N N

CuI, DBU; H2, Pd/C (80%) Tandem [3+2] O cycloaddition HO HO

OH OH O O HO O HO

OH OH O
N

OH O HO O O HO OH OH O OH O HO HO O HO OH O HO O HO

OH
N N N N

N

HO O HO HO OH OH O OH O O OH HO OH OOH

?-cyclodextrin
OH O OH O HO

HO OH O O

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

Azides: Applications in Total Synthesis
Ph toluene, OTMS 110 ° , C SEt 3h O O (86%) [3+2] N N cycloOMe N addition OBn MeO Me OBn MeO Me Ph OTMS SEt O H O H N N OMe N

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

Azides: Applications in Total Synthesis
Ph toluene, OTMS 110 ° , C SEt 3h O O (86%) [3+2] N N cycloOMe N addition OBn MeO Me OBn MeO Me Ph OTMS SEt O H O H N N OMe N OBn MeO Me Ph OTMS SEt O H O H N N OMe N

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

Azides: Applications in Total Synthesis
Ph toluene, OTMS 110 ° , C SEt 3h O O (86%) [3+2] N N cycloOMe N addition OBn MeO Me OBn MeO Me Ph OTMS SEt O H O H N N OMe N OBn MeO Me Ph OTMS SEt O H O H N N OMe N [-N2] Ph O H2N Me O mitomycin C N OCONH2 OMe NH NH3, MeOH O MeO H N O isomitomycin A OCONH2 OMe NH OBn MeO Me OMe OTMS SEt O H O N

(85%) Me Can you rationalize a mechanism?

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


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