Transcript Document

Stereoselective Routes to
Aziridines
Nate Bowling
McMahon Group
University of Wisconsin-Madison
Sept. 12, 2002
Summary
• Applications
– Uses for Optically Active Aziridines
• Addition of Nitrogen to Alkenes
– Nitrenes
– Atkinson-type Aziridinating Agents
– Asymmetric Aziridination Catalysis
• Aziridinations using Already Existing Stereocenters
– Sharpless Asymmetric Epoxidation and
Dihydroxylation
– Amino Alcohols
• Other Routes to Stereoselectivity
– Imines
– Michael Addition
– Azirines
• Resolution
R5
N
R3
R1
The Basics of Aziridines
R4
R2
• Ring Strain (SE) of 26.7 kcal/mol (R1-5 = H)
– Oxirane = 26.3 kcal/mol
– Cyclopropane = 27.5 kcal/mol
• Inversion barrier of nitrogen (R1-5 = H) = 18.9 kcal/mol
– Normal amines = 5- 6 kcal/mol
• Usually only susceptible to ring opening by nuclephilic attack
upon activation by:
– Protonation
– Quaternization
– Lewis acid adduct
– R5 = electron withdrawing substituent
Tanner, D. Angew. Chem. Int. Ed. Engl. 1994, 33, 599-619.
Nielsen, I. M. B. J. Phys. Chem. A 1998, 102, 3193-3201.
Bach, R. D.; Dmitrenko, O. J. Org. Chem. 2002, 67, 3884-3896.
Uses of Optically Active
Aziridines
Stereocontrolled Synthesis of Alpha and Beta Amino
Acids Through Aziridines
NucR2
N1
* 3 2*
R1
C-3 attack
Nuc
*
1
R
HNR2
*
CO2R3
 -amino acid
CO2R3
NucC-2 attack
(R2: electron-withdrawing group)
R2NH
*
R1
Nuc
*
CO2R3
 -amino acid
Dubois, L.; Dodd, R. H. Tetrahedron 1993, 49, 901-910.
Stereocontrolled Formation of β-Substituted Phenyl
Amino Acids
S
H3CO
Ph
O
OBzl
NHBoc
i) CH2Cl2, BF3.Et2O, p-MeOC6H5CH2SH, 67%
ii) (Boc)2O, TEA/THF, 90%
Ph
O
OBzl
N
H
NH2
BF3.Et2O, indole, 48%
CH2Cl2
O
Ph
HN
OH O
acetic acid, 70oC, 88%
OBzl
Ph
H2, MeOH, 10% Pd-C, 90%
O
Ph
OH
NH2
Xiong, C.; Wang, W.; Cai, C.; Hruby, V. J. J. Org. Chem. 2002, 67, 1399-1402.
OBzl
NHAc
Carbapenem Antibiotics Through a β-Lactam Ring
Closing
HO
LiEt2Cu, Et2O, 80%
N
Ts
OR
Et
RuCl3 (2 mol%) NaIO4
CCl4/CH3CN/H2O, RT, 82%
NHTs
OR
O
CO2H
N
H
HO2C NHTs
HO
DCC, 4-pyrrolidino-pyridine (cat.)
CH2Cl2, RT, 15 min, 83%
R = SiPh2tBu
Et
OR
Et
RuCl3 (2 mol%) NaIO4
CCl4/CH3CN/H2O, RT, 82%
OH i) Na-napthalene, DME, -78°C, 85% Et
ii) HCl, MeOH, RT, 91%
Et
O
R1
N
H
H
Me
O
O
N
S
NHR2
COOH
Thienamycin
PS-5
R1 = OH R2 = H
R1 = H
R2 = Ac
Tanner, D.; Somfai, P. Tetrahedron 1988, 44, 619-624.
OR
N
Ts
Proposed Mode of Action of Mitomycin C
O
CH2OC(O)NH2
H2N
OCH3
N
H3C
N H
Enz
Redn
OH
N
- MeOH
OH
DNA
CH2OC(O)NH2
O
H3C
OH
N
H3C
N
CH2OC(O)NH2
H2N
DNA
NH2
N H
OH
H2N
N
CH2OC(O)NH2
N
H3C
OH
H2N
OH
N H
H
H2N
OCH3
H3C
OH
H3C
CH2OC(O)NH2
H2N
O
O
NH2
Na, Y.; Wang, S.; Kohn, H. J. Am. Chem. Soc. 2002, 124, 4666-4677.
OH
NH2
Asymmetric Dihydroxylation with Aziridines
Ph
Ligand =
Ph
N
N
Ph
Ph
OH
OsO4, Ligand
Toluene, -78oC
OH
Yield = 90%
ee = 95%
OH
Ph
Ph
OsO4
OH
ent-Ligand
Ligand
OH
OsO4
OH
Ph
Ph
Tanner, D.; Harden, A.; Johansson, F.; Wyatt, P.; Andersson, P. G. Acta Chem. Scand. 1996, 50, 361-368.
Nitrenes
R N
Nitrene Addition in Accordance with Skell’s Rule
Singlet
Nitrene
Stereospecific
Addiditon
+
R N
+
Triplet
Nitrene
R N
H
H3C
H
H3C
R
N
R
N
CH3
H
H
CH3
Non-stereospecifc
Addition
+
+
H
H3C
H
H3C
R
N
R
N
CH3
H
H
CH3
+
+
H
H3C
H
H3C
R
N
R
N
McConaghy, J. S.; Lwowski, W. J. Am. Chem. Soc. 1967, 89, 2357-2364.
H
CH3
CH3
H
Different Reaction Pathways of Singlet and Triplet Nitrenes
EtO2CN3
h
EtO2CN
N
CO2Et
+
A
Mol % isoprene in
CH2Cl2
Yield %
Ratio A:B
100
95  2
1.17  0.05
30
86  3
1.21  0.03
2.5
87  1
1.45  0.02
0.5
85  2
2.13  0.05
N
CO2Et
Mishra, A.; Rice, S. N.; Lwowski, W. J. Org. Chem. 1968, 33, 481-486.
N
CO2Et
B
α-Elimination, Irradiation, and Thermal Syntheses of
Nitrenes
O
NsO
O2N
N
H
O
NEt3 or CaO or K2CO3
R
O
S
O
= Ns
h or 
O
N3
N CO2R
OR
Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. Tetrahedron Lett. 1993, 34, 4353-4354.
Fioravanti, S.; Pellacani, L.; Stabile, S.; Tardella, P. A. Tetrahedron 1998, 54, 6169-6176.
Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1997, 62, 4449-4456.
McConaghy, J. S.; Lwowski, W. J. Am. Chem. Soc. 1967, 89, 2357-2364.
Mishra, A.; Rice, S. N.; Lwowski, W. J. Org. Chem. 1968, 33, 481-486.
Highly Diastereoselective Nitrene Addition
PhO2S
O
N
O
Ph
a
O
b
yield (%)
de (%)
O
CO2Ra
NsONHCO2R
CO2Ra
CaO, CH2Cl2
91
99
90
99
92
97
90
98
N CO2Et
O
CO2Ra
N CO2t-Bu
O
CO2Rb
NsONHCO2R
CaO, CH2Cl2
O
CO2Rb
N CO2Et
O
R = Et, t-Bu
CO2Rb
N CO2t-Bu
Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A. J. Org. Chem. 2002, 67, 4972-4974.
The Thermolysis of Several Different Species Gives One
Common Nitrene
H
PhthalN N
R


PhthalN N SMe2
PhthalN N

N NPhthal
O
N
= Phthal
O
Atkinson, R. S.; Jones, D. W.; Kelly, B. J. J. Chem. Soc., Perkin Trans. 1 1991, 1344-1346.
Atkinson-type Aziridinating
Agents
O
O
N
O
R
N
NH2
N NH2
N
NH2
O
O
N NH2
N
R
N
O
NH2
Atkinson, R. S.; Rees, C. W. J. Chem. Soc. (C) 1969, 772-778.
Anderson, D. J.; Gilchrist, T. L.; Horwell, D. C.; Rees, C. W. J. Chem. Soc. (C), 1970, 576-579.
Oxidation of Atkinson-type Aziridinating Agents Gives
Stereospecific Addition
Stereospecific Addition
NR2 NH2
Pb(OAc)4
NR2 N
R1
R2
R3
R4
R1
R3
NR2
N
R2
R4
Singlet stabilized by resonance
N NR2
N NR2
Atkinson, R. S.; Rees, C. W. J. Chem. Soc. (C) 1969, 772-778.
Anderson, D. J.; Gilchrist, T. L.; Horwell, D. C.; Rees, C. W. J. Chem. Soc. (C), 1970, 576579.
Invertomers
X
N
R
H
cis-invertomer
R
N
X
H
trans-invertomer
When X is electron withdrawing, the inversion
barrier is decreased. When X is electron donating,
the inversion barrier is increased.
Atkinson, R. S.; Malpass, J. R. J. Chem. Soc., Perkin Trans. 1 1977, 2242-2249.
Kinetic v. Thermodynamic Invertomer Formation
O
Pb(OAc)4, -20oC
N NH2 +
Phthal
C6H5
O
o
CO2Me Pb(OAc)4, -20 C
+
H
N
H
>0oC
C6H5
H
Phthal
MeO2C
N
H
H
=
O
Top View
O
Phthal
H
N
H
MeO2C
H
Phthal
LTA = Lead Tetraacetate
H
>0oC
O
N
Phthal
H
N
H
O
N N
N N
O
O H
Atkinson, R. S. Tetrahedron 1999, 55, 1519-1559.
H
Non-bonding Interactions
O
OCH3
O
Pb(OAc)4
N NH2
O
O
N N
O
O
O
OCH3
N N
O
O
Carbonyl-Carbonyl interactions
O
O
O
Pb(OAc)4
N NH2
N N
O
O
O
N N
 -stacking
O
N NH2
O
O
+
O
Pb(OAc)4
//
Locked in s-trans conformation
Atkinson, R. S.; Grimshire, M. J.; Kelly, B. J. Tetrahedron 1989, 45, 2875-2886.
OCH3
Alternative Intermediate
Me
O
N
NH2
N
•
•
•
Oxidation with Pb(OAc)4 at –20oC, and subsequent examination by NMR
spectroscopy at -30oC revealed no presence of aziridine, but amino protons had
disappeared.
Removal of Pb(OAc)4 from solution revealed the presence of a methyl singlet that
had previously been overshadowed by the Pb(OAc)4 acetate signal.
Surmised that the reacting intermediate may not be nitrene, but acetoxyamino group
instead.
O
N
OAc
NH
Me
N
Atkinson, R. S.; Grimshire, M. J.; Kelly, B. J. Tetrahedron 1989, 45, 2875-2886.
Mechanistic Pathway from Proposed
Intermediate
Me
Me
O
O
Q
H
Q
O
N
O
Ph
O
H N
H3CO
O
N
Q=
N
R
Atkinson, R. S.; Williams, P. J. J. Chem. Soc., Perkin Trans. 1 1996, 1951-1956.
Support for the Proposed Mechanism
H3C
Et
N
H3C
O
Et
O
N N H
O
N
+
CO2Me
H3C
H3C
Et
O
O
Et
H
O
N N H
O
N
H
H
HO
i
O
O
O
O
MeO
+
H
i
Pr
OH
MeO2C
Pr
High diastereoselectivity
Low diastereoselectivity
Departure of Acetate
facilitated by alchol
Departure not facilitated
by alcohol
Atkinson, R. S.; Williams, P. J. J. Chem. Soc., Perkin Trans. 1 1996, 1951-1956.
O
N N H
O
N N H
iPr
O
MeO
N
O
HO
iPr
Stereochemical Control with the Aziridinating Agent
Me
N
OSiMe2tBu
N
Ph
+
Ph
H
TMS
NH2
O
Q*
N
H
TMS
d.r. 11:1
Me
N
Q* =
OSiMe2tBu
N
O
Atkinson, R. S.; Coogan, M. P.; Lochrie, I. S. T. Tetrahedron Lett. 1996, 37, 5179-5182.
Diastereoselectivity Using Oppolzer’s Auxiliary
R1
O
NH
SO2
+
R2
Cl
R1
O
R2
N
SO2
R3
R3
O
OAc
N NH
O
O R1
O
R2
O R1
Ti(OiPr)4
Xc
N NPth
R3
O R1
R2
+
Xc
N Phthal
R3
R3
(major)
R2
N Phthal
(minor)
R1
R2
R3
% Yield
% de
H
H
H
94
78
H
Ph
H
90
80
Kapron, J. T.; Santarsiero, B. D.; Vederas, J. C. J. Chem. Soc., Chem. Commun. 1993, 1074-1076.
Asymmetric Aziridination
Catalysts
Catalytic Aziridination via Nitrenoid Intermediate
L*Cu+ PF6R1
R3
PhI=NTs
R2 N
Ts
R1
R3
PhI
R2
[L*Cu=NTs]+
PF6
Nitrenoid intermediate allows for asymmetric aziridination under the influence of L*
Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5889-5890.
Jacobsen Asymmetric Aziridination Catalyst
O
Me
Me +
O
PhI=NTs
L*.CuPF6
25oC
PhI +
NC
NC
Me
Me
N
Ts
aziridine ee (%): 82-85
Cl
H
N
H
N
Cl
L* =
Cl
Cl
Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5889-5890.
Enantioselective Katsuki Aziridination Catalyst
Ts
+
PhI=NTs
catalyst (5 mol%), 4-phenylpyridine N-oxide
substrate-CH2Cl2 (5:1)
Me
Me
N
N
Mn
O
O
Ph Ph
AcO-
Substrate
Yield (%)
% ee
Styrene
76
94
p- chlorostyrene
70
86
p-methylstyrene
75
81
Nishikori, H.; Katsuki, T. Tetrahedron Lett. 1996, 37, 9245-9248.
N
Stereoselective Routes to
Aziridines Using Sharpless
Asymmetric Epoxidation and
Asymmetric Dihydroxylation
Catalysts
Sharpless Asymmetric Epoxidation
(-)-tartrate
O
OH
R
R
OH
N
H
OH
AE
R
H
N
(+)-tartrate
R
(+)-tartrate
OH
O
R
O
R
OH
R
R
OH
OH
OH
N
H
AE
(-)-tartrate
H
N
R
OH
O
Tanner, D. Angew. Chem. Int. Ed. Engl. 1994, 33, 599-619.
R
OH
Epoxide to Aziridine via Staudinger reaction
RO
H
NaN3
O
RO
H
OH
N3
RO
+ H
N3
OH
PPh3
CH3CN
reflux
RO
H
RO
H
RO
H
O
PPh3
N
H
+
H
N
PPh3
O
RO
H
OH
N PPh3
+
RO
H
N PPh3
OH
NH
Sommerdijk, N. A. J. M.; Buynsters, P. J. J. A.; Akdemir, H.; Geurts, D. G.; Nolte, R. J. M.; Zwanenburg,
B. J. Org. Chem. 1997, 62, 4955-4960.
Epoxide to Aziridine via Aza-Payne Reaction
O
H
Ph
H
N
O
Ts
NH
5% aq. NaOH solution
reflux
5 min
HO
H
OH
N
i
OH
Ti(O- Pr)4
THF, 0oC
63%
N Ts
Ph
OH
Urabe, H.; Aoyama, Y.; Sato, F. Tetrahedron 1992, 48, 5639-5646.
Moulines, J.; Charpentier, P.; Bats, J.-P.; Nuhrich, A.; Lamidey, A.-M. Tetrahedron Lett. 1992, 33, 487490.
Retention of Epoxide Configuration
O
OH
ArSNa
R1
2
ArS
R
R1
HO
+
R2
R2 1
R
SAr
TsNH2, BF3.Et2O
NHTs
ArS
Me
R1
R2
TsHN
+
R2 1
R
SAr
Me
TsHN
NHTs
Me3O+ BF4ArS
R1
2
R
+
R2 1
R
SAr
NaH
Ts
N
R1
R2
Toshimitsu, A.; Abe, H.; Hirosawa, C.; Tamao, K. J. Chem. Soc., Perkin Trans. 1 1994, 3465-3471.
Sharpless Asymmetric Dihydroxylation
AD-mix- 
HO
OH
R
R'
R
R'
HO
OH
SOCl2
O
O
S
O
O
R
R'
R
R'
RuO4
O
S
O
R'
O
1) LiN3
R
R'
R
R'
R
2) LiAlH4
N
H
1) LiN3
H
N
R'
R
AD-mix- 
SOCl2
RuO4
O
S
O
O
O
O
S
O
O
Tanner, D. Angew. Chem. Int. Ed. Engl. 1994, 33, 599-619.
2) LiAlH4
R
R'
Different Pathways From Homochiral 1,2-Cyclic
Sulfates
OH
R''
R'
OH
O
1) SOCl2
R'
2) RuO4
O
S
O
R''
R" 1) LiAlH , THF, 
4
N
H
2) 20% KOH
80-88%
R'
NH2R
O
LiN3, THF
R'
RNH2
THF, 
R'
OSO3R''
n-BuLi or
LiAlH4, THF, 
or NaOH, 
1) 20% H2SO4
2) NaOH
OSO3-Li+
R''
N3
OH
R''
R'
NHR
74%
R'
R"
N
R
62-89%
Lohray, B. B.; Gao, Y.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 2623-2626.
Chiral Aziridines from Amino
Alcohols
Okawa’s Aziridination Procedure From Amino
Alcohols
H2C OH
H2N C COOBzl
H
Tri-Cl
H2C OH
Tr N C COOBzl
H H
Ts-Cl
Pyridine
H2
C
Tr N C COOBzl
H
Nakajima, K.; Takai, F.; Tanaka, T.; Okawa, K. Bull. Chem. Soc. Jpn. 1978, 51, 1577-1578.
Mitsunobu Reaction: Amino-Alcohol to Aziridine
R2
R2
H
H
R1 N C C OH
R3 R4
DEAD, P(Ph)3
R1 N
R3
R4
R1
R2
R3
R4
time/solvent
Yield (%)
C6H5CH2
H
H
CH3
2 h/ether
90
C6H5CH2
CH3
CH3
H
18 h/ether
89
Pfister, J. R. Synthesis 1984, 969-970.
Preparation of Aziridines from the Mitsunobu Reaction of
1,2-Aminoalcohols
O
Bn
O
N
H
H
N
O
O
N
H H
OH
H3C OH
CH3
O
H
HN
CH3
N
N
H
H H
O
Bn
O
O H C OH
3
Ph3P, DIAD
CH2Cl2, 0oC
Bn
O
O
N
H
N
O
H3C H
N
H H
CH3
56%
O
Ph3P, DIAD
THF, 0oC
N
Bn
84%
O
HN
O
O H3C H
Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267-6270.
N
H H
CH3
Stereoselective Formation of
Aziridines from Imines
General Mechanism of Aziridine Formation from Imines
From alpha-halo enolates
R"
N
M
R"
O
OR
R'
N
M
R"
O
R'
N
OR
O
R'
OR
X
X
From sulfonium ylides
R"
R'
R"
N
H
C
Ph
SR2
R'
R"
N
Ph
SR2
N
R'
Ph
High Diastereoselectivities From Sulfinimines in an
Aza-Darzens Reaction
X
OR2
H
OM
H
O
p-Tolyl
X = Br
R2 = Me, t-Bu
S
N
OMe
Br
CO2R2
H N H
S
p-Tolyl
O
CO2R2
H
+
R1 N H
S
p-Tolyl
O
Major
R3
R1
R1
Ph
R3
OLi
1
R = Ph
H N CO2Me
S
p-Tolyl
O
Major (R3 = H)
Ph
+
CO2Me
H N R3
S
p-Tolyl
O
R1
R3
R2
Conditions
% de
Yield (%)
Ph
H
Me
LiHMDS/78/2.5h
98
70
p-MeOPh
H
Me
LiHMDS/78/2.5h
98
74
Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang, Y. J. Org. Chem. 1999, 64, 7559-7567.
Rationale for Diastereoselectivity
Ph
Ph
OMe
Li
OMe
Li
N
Br
O
S
H
S Br
O
Ph
CO2Me
N
H
Ar
Ph
H
S
p-Tolyl
Me
O
Ar
O
N
Me
N
CO2Me
S
O
p-Tolyl
O
Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang, Y. J. Org. Chem. 1999, 64, 7559-7567.
Enantioselectivity Using the Imino Corey-Chaykovsky
Reaction
p-Tolyl
OH
1
R CH2Br
+
R2CH=NR3
S
R2
base, solvent
R3 = Ts
H
H
N H
R1
R1
R2
Yield (%)
trans:cis
Trans ee(%)
Ph
Ph
>99
75:25
92
P-NO2C6H4
Ph
>99
65:35
98
Saito, T.; Sakairi, M.; Akiba, D. Tetrahedron Lett. 2001, 42, 5451-5454.
Highly Diastereoselective Aziridination of Imines
with Trimethylsilyldiazomethane
N
R2
+
SiMe3
1,4-dioxane
40oC, 3-15h
R2 = Ts
N2
R1
R2
N
R1
R1
Yield (%)
cis:trans
Ph
72
95:5
P-OMePh
65
100:0
SiMe3
Aggarwal, V. K.; Alonso, E.; Ferrara, M.; Spey, S. E. J. Org. Chem. 2002, 67, 2335-2344.
Ring Closing Pathway
N
R2
SiMe3
+
N2
R1
H
N2
Me3Si
N
R1
ring closure
R2
H
H migration and
protodesilylation
R2
N
R1
N
SiMe3
R2
R1
Aggarwal, V. K.; Alonso, E.; Ferrara, M.; Spey, S. E. J. Org. Chem. 2002, 67, 2335-2344.
Rationale for Cis-Selectivity
N
R2
SiMe3
+
N2
R1
H
N2
Me3Si
N
R1
R2
H
R2
N2
H
N
R
1
R2
N
H
R1
TMS
cis
SiMe3
+
N2
R2
H
H
N
N2
trans
R1
TMS
Aggarwal, V. K.; Alonso, E.; Ferrara, M.; Spey, S. E. J. Org. Chem. 2002, 67, 2335-2344.
Utilization of Michael Addition
in Aziridine Synthesis
Highly Diastereoselective, Auxiliary Mediated,
Gabriel-Cromwell reaction
O
Br
Br2
N
H
S
O O
O
O
*
N
Br
S
O O
Et3N
N
Br
S
O O
RNH2
R
N
O
SN2
RNH
N
H
S
O O
si-face
protonation
O
H
H
R N
O
N
N
H Br
S
O O
Br
R = Bn (86%),100%selectivity
R = p-C6H4OMe (89%) dr = 9:1
R = H (60%), 100%selectivity
Garner, P.; Dogan, O.; Pillai, S. Tetrahedron Lett. 1994, 35, 1653-1656.
S
O O
Aziridines from Azirines
Synthesis of Optically Active Azirines via the Neber
Reaction
General
O
O
R
OR'
1) NH2OH.HCl, NaOH
MeOH/H2O
2) TsCl, pyridine
CH2Cl2
TsO
R
N
O
N O
NEt3
CH2Cl2
OR'
R
OR'
Enantioselective
TsO
R
N
N O
O
R
OR'
*
OR'
TsON
H
HO
H
N
HH
HO
H
OCH3
N
KHCO3 + KOTs
OCH3
N
K2CO3 (s)
Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491-8492.
Enantioselective Conversion of Neber Derived
Azirines to Aziridines
O
R
O
OR'
1) NH2OH.HCl, NaOH
MeOH/H2O
2) TsCl, pyridine
CH2Cl2
TsO
N
R
O
N O
Base
R
OR'
R
R’
Base
Yield (%)
ee (%)
Me
Me
Quinidine
40
81 (R)
Me
Et
Quinidine
43
82 (R)
N
R
COOR'
H
NaBH4
R
H
OR'
H
N COOR'
H
Exclusive formation of cis-aziridine carboxyic esters
Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491-8492.
Optically Active Aziridines via
Resolution
Optical Resolution by Complexation with Optically
Active Compounds
OH
Ph
C
Ph
Ph C
Ph
OH
OH
Ph
Ph C
Ph C
Ph
OH
O
O
R N
R N
1a
R N
Me
2a R = Et
2b R = nPr
O
CO2Me
CO2Me
CO2Et
2c R = Et
2d R = nPr
2e R = nPr
2f R = iPr
O
1b
2a
2b
2c
2d
2e
2f
host
1a
1a
1b
1b
1a
1a
yield (%)
34
32
43
44
28
33
Mori, K.; Toda, F. Tetrahedron: Asym. 1990, 1, 281-282.
% ee
100
not determined
64
100
100
100
Optical Resolution Through Lipase-Catalysed
Alcoholysis
O
O
OR2
N
R1
R1
CH3
iso-Pr
iso-Pr
iso-Pr
iso-Pr
R2
CH3
CH3
CH3
CH2CF3
CH2CF3
Lipase
Hexane, 40oC
n-Butanol
Lipase
PPL
PPL
CCL
PPL
CCL
Rxn time
(days)
2
42
5
48
10
N
R1
*
O
OR2
ee substrate
62.3
5
21
10
91
+
N
R1
ee product
66
54.5
32
>95
68
PPL = pig pancreatic lipase
CCL = Candida cylindracea lipase
Martres, M.; Gil, G.; Meou, A. Tetrahedron Lett. 1994, 35, 8787-8790 .
*
O-nBu
Total
yield (%)
95
50
61
73
90
Review of Routes to Chiral Aziridines
• Addition of Nitrogen to Alkenes
– Nitrenes
– Atkinson-type Aziridinating Agents
– Asymmetric Aziridination Catalysis
• Aziridinations using Already Existing Stereocenters
– Sharpless Asymmetric Epoxidation and
Dihydroxylation
– Amino Alcohols
• Other Routes to Stereoselectivity
– Imines
– Michael Addition
– Azirines
• Resolution
Acknowledgements
• People who attended my practice talk:
-
Jodie Brice
Matt Bowman
Reagen Miller
Greg Hanson
Jeff Johnson
Seol Kim
Beatriz DeGuia
Wendy deProphetis
Susie Przbylinski
• Special thanks to:
– Wendy (computer, abstract)
– Greg (abstract)
– Juli