Aziridines in Synthesis
Baran Lab
More S character of the lone pair which results in lower basicity and reduced
π-donor ability. Upon ring opening aprox. 25 kcal/mol is released.
Aziridines can be synthesized in numerous ways including SN2 displacement,
1-4 addition, addition of carbenes, electrophiles, nitrenes and reduction
H
Activated aziridines
R = CO2R, SO2R and COR
N
R
pKa = 8
N
Non-activated aziridines
R = H, Alkyl and Aryl
O
pKa = 10.98
N
H
EtO2C
Cl
HO
H2SO4, 71%
N
R
NH3
H. Wenker. JACS. 1935, 2328.
There has since been developed a waste arsenal of synthetic methods to make
chiral aziridines, from chiral starting materials over chiral auxilaries to
asymmetric catalysis.
O
O
NaOH, 27% N
O3SO
OMe
R'Li
H
O
NH2
N
R'
O
CO2Et
N
O
NH2
S
O
The pyrimidal inversion of nitrogen in the aziridines (8-12 kcal/mol) are higher in
energy than for open chained amines. Separate NMR spectras can be observed.
Certain N-chloro- and N-alkoxyaziridines are chiral.
R
M. Jessing
Li
N
R
R'
S. Wattanasin and F. G. Kathawala. Tet. lett. 1984, 811.
Ph
CO2H TsCl,
DIPEA
96%
NH2
Unprotected amino aldehydes
CO2H
Ph
NHTs
i LiAlH4
ii TsCl, Et3N
90%
Ph
NTs
M. B. Berry and D. Craig. Synlett. 1992, 41.
NH
O
NH
OH
N
CHO
R
OH
S.A.E.
R
O
OH
R. Hili and K. Yudin. JACS. 2006, 14772.
i NaN3
ii TBSCl
iii PPh3
iv TBAF
82%
R
HN
OH
D. Tanner and P. Somfai. Tet. lett. 1987, 1211.
O
NH
OH
H 3O+
R
H 2O
N
R
N
R
NH2
O
BuLi
AlMe3
72%
NH
OH
R. Najime, S. Pilard and M. Vaultier. Tet. lett. 1992, 5351.
1
Aziridines in Synthesis
Baran Lab
i ArSNa
ii TsNH2, BF3.OEt2
iii Me3O+BF4iv NaH
66-94%
O
R1
R2
Ts
N
R1
N
R
O
OH
R2
R1
O
S
O
R1
OH
OSO3
RNH2
O
nBuLi or
LiAlH4 or
NaOH
62-89% R1
-
R2
R1
R2
NHR
O
NAux*
RNH2
NR
Base
R
NAux*
H
Br
Br
OMe
S
Br
NH
Br
O
R
H
CO2Me
N
SOTol
R2
S
Tol
64-77%, >94% de
F.A. Davis, PZhou and G.V. Reddy. JOC. 1994, 3243.
RN
O
R
OLi
Li
H
HO
NHR O
OMe
O
B. B. Lohray, Y. Gao and K. B. Sharpless. Tet. lett. 1989, 2623.
R
R
O
Tol
R2
A Toshimitsu, H. Abe, C. Hirosawa and K. Tamao. J. Chem. Soc., Perkin Trans I.. 1994, 3465
i SOCl2
ii RuO4
M. Jessing
N
CO2R'
R
NAux*
TsCl,
N
Chiral R
CO2R'
tertiary
base
4 H
R
NaBH4
NH
H
CO2R'
1 H
60-89%, >90% de H
P. Garner, O. Dogan and S. Pillai. Tet. lett. 1994, 1653.
G. Cardillo,S. Casolari, L. Gentiluca and C. Tomasini. Angew. Chem. Int. Ed. Engl. 1996, 1848.
R1
O
R1
R
H
N
H
OAc
N
Organocatalyst
54-68%, 4-10:1 dr
84-99% ee
O
R
H
M. M. H. Verstappen, G. J. A. Ariaans and B. Zwanenburg. JACS 1996, 8491.
R1 = Cbz or Boc
J. Vesely, I. Ibrahem, G.-L. Zhao, R. Rios and A. Córdova. Angew. Chem. Int. Ed. Engl. 2006, Early view.
O
O
O
N
Dpp
NAux*
Br
R
H
O
Dpp
NaHMDS
40-78%,
>95% de
only cis
Cl
N
R
N
O
H
NAux*
H
J. B. Sweeney, A. A. Cantrill, A. B. McLaren and S. Thobhani. Tet. 2006, 3681.
O
O
Cl
O
StBu
O
O
CN
N
H HCl
∆
N
83%, >96% ee
J.-L. Vaerman and H. G. Viehe. Tet. 1989, 3183.
NC
StBu
2
Aziridines in Synthesis
Baran Lab
Ph
CuOTf
PhI=NTs
Chiral Ligand
75%, >98% ee
O
O
NC
N
R1
NC
Bn
N
Me
N
R2
N
O
OEt
T. B. Sim, S. H. Kang, K. S. Lee and W. K Lee. JOC. 2003, 104.
both high de and ee can
be achived w. VAPOL
N
NHR
NR2R3
For nonactivated aziridines ring opening is borderline between SN1 and SN2.
Ph
N
R1
F
Ph
R2
H
R
HNR2R3
10% BiCl3 or
10 % B(C6H5)3
93-99%
N. R. Swamy and Y. Venkateswarlu. Synth. Commun.. 2003, 547.
I. D. G. Watson, Ak. K. Yudin. JOC. 2003, 5160.
K. B. Hansen, N. S. Finney and E. N. Jacobsen. Angew. Chem. Int. Ed. Engl. 1995, 1676.
J. C. Antilla, W. D. Wulff. JACS 1999, 5099.
HF .pyr
60%
N
Me
O
CO2Et
R1
N
O
O
N2CHCO2Et
R1
MeO2CCl
CH3CN
92%
OEt
Ph
H
Ph
R2
Ph
N
NTs
Bn
D. Tanner, P. G. Anderson, A. Harden and P. Somfai. Tet. lett. 1994, 4631.
N
R1
Ph
CuOTf, PhINTs
68%, 90% ee
R2
OR
H
H
Ph
PhHN
B. A. B. Prasad, G. Sekar and V. K. Singh. Tet. lett. 2000, 4677.
Bn
Bn
H
R2
ROH
Sn(OTf)2 or
BF3OEt2
66-92%
NH
Z. Li, K. R. Conser and E. N. Jacobsen. JACS 1993, 5326.
H
M. Jessing
Ph
H
NH2
PhHN
H2, 20% Pd(OH)2/C
93-99%
Ph
R1
R2
H
H
T. Satoh, R. Matsue, T. Fujii and S. Morikawa. Tet. 2001, 3891.
H
T.N. Wade. JOC. 1980, 5380.
OBn
PhSe
OBn
OBn
BnO
NH
AcOH
67%
N
BnO
NHAc
R
R
N
H
OH
O
H. Dehmlow, J. Mulzer, C. Seilz, A. R. Strecker and R. Kohlmann. Tet. lett. 1992, 3607.
PhSeH
65-96%
OH
AIBN
R
Bu3SnH
80-96%
HO
trans 10:1 cis
N
H
M. Besev and L. Engmann. Org lett. 2002 3023.
3
Aziridines in Synthesis
Baran Lab
R2
Pd(OAc)2
PPh3
R2
N
R1
Pd(Ph3P)2
N
R1
For activated aziridins ring opening is normally through SN2 at the least hindered
ring-carbon and for fused bicyclic systems via Fürst-Plattner diaxial opening
Y
X
C
Y
Br
X
34-97%
N
R2
MgBr
CO2R' quant.
H
R1
R
D. C. D. Butler, G. A. Inman and H. Alper. JOC. 2000 5887.
B. M. Trost, D. R. Fandrick. JACS. 2003 11836.
N
Bn
H
NaBr
Amberlyst 15 R
quant.
N
H
i EtMgBr
ii ICH2CH2CH2I
iii NaB(AcO)3H
42%>95% de
N
Bn
AcOH
Pr
N
Ph
Me
NHTs
45-89%, 0-91% ee
R
P. Muller and P. Nury. Helv. Chem. Acta. 2001, 662.
O
FVP
350 oC, 0.05 torr
84%
RMgBr
Cu(OTf)2
Chiral ligand
Ts
H
CO2Et
N
NHCO2Et
100%
N
H
Me
H
N
J. F. Hayes, M. Shipman and HTwin. Chem Commun. 2001 1784.
CO2Et
N Bu
AcO
Ph
Ph
H. Takeuchi and K. Koyama. J. Chem. Soc. Perkin Trans 2. 1981, 121.
Ph
H
Br
G. Richi, R. D'Achille and C. Bonini. Tet. lett. 1996, 6893.
CO2Et
Ph
CO2R'
O
H
O
NHCO2Et
NHCO2Et
V. Mahadevan, Y. D. Y. L. Getzler and G. W. Coates. Angew. Chem. Int. Ed. Engl. 2002, 2781.
H
CO2R'
R
H
N
CO2Et
Co2(CO)8
CO, DMF
Chrial Ti
catalyst
80%
M. Jessing
R
N
N
H
Tol
S
R
CO2Me
N
Bu
NH2
TFA, 0oC
72%
NH2
O
R
o
TFAA, 35 C
59%
R
H
CO2Me
OH
Ph
CO2Me
OH
CO2Me
B. R. Henke, A. J. Kouklis and C. H. Heathcock. JOC. 1992, 7056.
O
O
F 3C
S
N
H
Tol H
F. A. Davis and G. V. Freddy. Tet. lett. 1996, 4349.
4
Aziridines in Synthesis
Baran Lab
O
Lewis Acid
microwave
toluene
O
Ph
N
N
Ts
InCl3
N
H
Ph
O
N
Ph
(60:40 of regioisomers)
O
O
N
N
NH2
N
M. Jessing
N
O
O
N
NH
HN
Ph
Boc
O
Ph
O
2
O
3
N
H
85%
J. S. Yandav, B. V. S. Reddy, S. Abraham and G. Sabitha. Tet. lett. 2002, 1565.
H
R
Mts
R1Cu(CN)M
C
NH
R
H
R
R1Cu(CN)M
N
H
N
Mts
R1
R
Mts
Mts
72-99%
C
NH
R1
H
G. Cardillo, L. Gentilucci, M. Gianotti and A. Torlomelli. Synlett. 2000, 1309.
H. Ohno, A. Toda, N. Fujii, Y. Takemoto, T. Tanaka and T. Ibuka. Tet. 2000, 2811.
Me
Me
Ts
N
Ph
Ph
BF3OEt2
Me
Me
96%
Me
Ph
Ph
H
Me
Ts
H
N
LDA
95%
N
Me
Me
Me
CO2tBu
Me
N
H
CO2tBu
J. Åhman and P. Somfai. JACS. 1994, 9781.
A. Mordini, L. Sbaragli, M. Valacchi, F. Russo and G. Reginato. Chem Commun. 2002 778.
H
R1
N
Ts
R1
TMSX
5% TBAF
60-99%
H
X = CN, N3, Cl
R2
R2
OBn
NHTs
Bn
N
X
O
J. W. Wu, X.-L. Hou and L.-X. Dai. JOC. 2000, 1344.
LiHMDS
81%
OBn
N
H
O
Bn
U. M. Lindström and P. Somfai. JACS. 1997, 8385.
R2
TsHN
R1
OR
BF3OEt2
ROH
>92%
R2
R1
N
Ts
CAN
MeOH
70-95%
R2
TsHN
R1
N
OMe
low regioselectivity
NaN3 and H2O
can be used too
B. A. B. Prasad, G. Sekar and V. K. Singh. Tet. lett. 2000, 4677.
S. Chandrasekhar, C. Narsihmulu and S. S. Sultanai. Tet. lett. 2002, 7361.
Ts
HO
OR
Red.Al or
LiAlH4 or
LiMe2Cu
NH2
H
HO
OR
R'
H
R' = Me or H
D. Tanner. Angew. Chem. Int. Ed. Engl. 1994, 599. and ref. cited therein
5
Aziridines in Synthesis
Baran Lab
M. Jessing
Ts
R1
R2
Ts
NHTs O
SmI2, DMEA
MeOH or THF
O 70-98%
N
R1
R2
R2
X
NHTs
Te2(Te, NaBH4, DMF) R2
74-90%
R1
N
OTs
R1
X
R3
R3
G. A. Molander and P. J. Stengel. Tet. 1997, 8887.
B. Chao and D. C. Dittmer. Tet. lett. 2001, 5789.
Ts
H
N
Ts
N
Et3B
Reactions on aziridines without ring opening.
O
94% ee
O
I
HO
I
nBu
61%, 93% ee
O
H
H
nBu
N
nBu
i LHMDS
ii RCHO
HO
O. Kitagawa, S. Miyaji, Y. Yamada, H.Fujiwara and T. Taguchi. JOC. 2003, 3184.
O
H
H
nBu
N
R
nBu
HO
H
nBu
N
R
O
Me
H
O
Me
Me
only syn products
R1
N
R1
TMS
AcO
D. Tanner, C. Birgersson, A. Gogoll and K. Luthman. Tet. 1994, 9797.
Ts
Pd(PPh3)4, P(OPr-i)3
BuLi, 31-82%
R2
R2
N
Ts
S.J. Hedley, W. J. Moran, A. H. G. P. Prenzel, D. A. Price and J. P. A. Harrity. Synlett. 2001, 1596.
H
H
R
TMS
R1
N
Ts
LiO
TMS
R1
R2
R1
O
+
ii H or RCHO
36-80%
R2
N
Bn
Li, DTTB
55%
Ns
N
R2
Ts
N
Alkyl
I
H
H
N
H
Me
Mg, MeOH
sonication H
75%
H
CO2Cy
N
H
Ts
D. A. Alonso and P. G. Andersson. JOC. 1998, 9455.
N
Ts
Tol
H
2 eq. Indium
MeOH, ∆
82-96%
Bn
CO2Cy
O
or
K. Iwamoto, M. Kojima, N. Chatani and S. Murai. JOC. 2001, 169.
Ts
N
Me
S
O
NHTs
Ph
Alkyl
N
Ph
J. S.Yandav, A. Bandyopadhyay and B. V. S. Reddy. Synlett. 2001, 1608.
Me
i MeMgX
tBuLi
ii E+
43-96%
H
Ph
R
N
Me
R = D, CHOHPh,
CO2Et, PO3Et2
Ph
T. Satoh, M. Ozawa, K. Takano and M. Kudo. Tet. lett. 1998, 2345
6
Aziridines in Synthesis
Baran Lab
H
N
MeO2C
H
Ph
H
i DMSO, (COCl)2
ii Et3N
60%
MeO2C
N
Ph
H
S
S
M. Jessing
i tBuLi
ii chrial epoxide
iii chrial aziridine
56%
S
S
TBSO
L. Gentilucci, Y. Grijzen, L. Thijs and B. Zwanenburg. Tet. lett. 1995, 4665
TBS
NHTs
TBSO
Bu
Et
i TBAF
ii MsCl
iii K2CO3, then
5% Na-Hg, Na2HPO4
93%
Aziridines used in synthesis
N2CHCO2Et
N
Ar
Bn
Bn 10% (S)-VAPOL
H
N
B(OPh)3
80%, 30:1 dr
96%ee (99% ee) EtO C
Ar
2
S
Raney Ni, H2
69%
OH
N
i Cl2CHCO2H
HO
ii NaBH4
59% (>99%ee) Cl2HC
NO2
N
Bu
Et
NH
S
Bu
Et
(-)-Indolizine 233AB
O
A. B. Smith III and D.-S. Kim. JOC. 2006, 2547
(-)-chloramphenicol
C. Loncanic and W. D. Wulff. Org. lett. 2001, 3675
EtO
O
i mCPBA
ii H2, Pd(OH)2/C
iii TsCl
iv BnNH2
68%
i BnO(CH2)4MgBr
ii DIBAL
iii TBSCl
81%
O
O
O
OBn
O
OTBS
BnHN
OTBS
i RuCl3 O S O
NaIO4
15 sec. O
ii SO2Cl2
79%
TsN
O
O
i BzONH4
ii H3O+
iii TBSCl HO
iv NaOMe
57%
TsN
NH
OH
perhydrohistrionicotoxin skeleton
D. Tanner and P. Somfai. Tet. 1986, 5657
HO
OTBS
O
N
O
H
OTBS
O
i tBuLi
ii ArCH2Br
68%
OTBS
Bn
O
TsN
i Toluene, ∆
ii MeLi, MsCl
i LiBu2Cu
ii Fiii H2, Pd(OH)2/C
27%
OTBS
O
O
NTs
Me2AlCl
68%
O
O
O
Ar
NTs
Toward 7-epi-Deoxypancrastatin
U. Rinner, P. Siengalewicz and T. Hudlicky. Org. lett. 2002, 115
7
Aziridines in Synthesis
Baran Lab
SEM
SEM
O
Me
O
Me
N
H
Me
O
Na2[Fe(CO)4]
CO, 54%
N
M. Jessing
H
O
i PPh3
ii NaBH4
Me 90%
H
O
H
N
N
N3
MeO2C
H
O
H
NH
Me
OMe
O
O
I2
25 %
L. E. Overman and M. J. Sharp. JOC. 1992, 1035.
O
N
Ar
Y(OiPr)3
TMSN3
CH3CH2CN
96%, to 99%ee
O
NHBoc
NC
i DEAD,
ii ROH,
BF3OEt2
45%
NC
NHBoc
H
N
N3
OH
i Boc2O
ii NaOH
iii PPh3
Ar iv Boc2O
88%
Me
O
H
i SeO2, DMP
ii DMP
68%, >99% ee
O
O
NHBoc
NHBoc
O
Ar1
Ar3
Ar2
Br
R
+
N
O
F
HO
F
Ar2
NaBH4
N
R
Chiral ligand
NH2 H3PO4
Y. Fukuta, T. Mita, N. Fukuda, M. Kanai and M. Shibasaki. JACS. 2006, 6312.
Ar1
R
H
N
H
Br
Ar1
Ino
Ar3
Ar2
R
H
Ar3
Ar2
R
O
Ar3
Ar2
Ar1
Ar3
OH
NHAc
EtO2C
H
D. R. Williams, D. L. Brown and J. W. Benbow. JACS. 1989, 1923.
HO
Tamiflu
Me
N
O
NHBoc
Ph2OP
O
H
H
O
Croomine
NHBoc
i TMSCN,
Ni(COD)2
NHBoc ii NBS
iii LiAlH(OtBu)3
60%, >20:1
H
O
NHBoc
Ar1
i TFA
ii Boc2O
iii Ac2O
iv HCl
v H3PO4
14%
Me
O
N
H
Br
OH
Ar1 H
Ar3
Ar2
N
OH
R
N
H
OH
P. S. Baran and N. Z. Burns. JACS. 2006, 3908.
8
Aziridines in Synthesis
Baran Lab
M. Jessing
Aziridine containing natural product
NHTr
O
Bn
NHBn
OMe
tBuO2C
OMe
N
R
Bn
N
BnN
H
O
Li
OH
O
R
O
N
OMe
NHTr
Ts
N
H
N
N
O
Bn
TMS
6 steps
46%
OMe
Bn
AcO
OAc
N
N
H
i DIBAL
ii FeCl3
86%
Ts H
N
OMe
CO2Me
H
OTBS
OMe
N
OMe
CH2OTBS i DMP
i AgOTf
ii BnMe3NCN
40%
N
C3H5O
i Me3NBH3, TFA
ii BuLi
iii MeI
iv Cp2ZrCl2, BuLi
v DIAD, MeI
vi HF pyr
61%
i FVP
ii LHMDS
MeOCH2Br
73%
O
NMe
O
CH2OH
ii LiR
iii Ac2O
85%
N
NMe
NTr
O
R
DEAD
71%
N
C3H5O
ii AcOH
93%, 6:1 dr
OMe
82%
OC3H5
NMe
O
N
I
I
O
i NaOH
ii TPAP
iii O2, Co2
iv HF pyr
v Fmoc-N=C=O
vi Et3N
25%
CO2Me
Bicyclic core of Sarain
H
OMe
O. Irie, K. Samizu, J. R. Henry and S. M. Weinreb. JOC. 1999, 587
O
O
O
H2N
N
NMe
6-Desmethyl-(methylaziridino)mitosene
O
E. Vedejs, A. Klapars, B. N. Naidu, D. W. Piotrowski and F. C. Tucci. JACS. 2000, 5401
9