the [3+2]cycloaddition reaction - university of...
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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]