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REVIEW
1347
Recent Synthetic Applications of Chiral Aziridines
William McCoull,a Franklin A. Davisb*
a
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Department of Chemistry, Temple University, Philadelphia, PA 19122−2585, USA
Fax (215) 2040478; E-mail: [email protected]
Received 7 June 2000
b
Abstract: Due to their ready availability in chiral form, and propensity to undergo regio- and stereoselective ring opening, aziridines
have found widespread use in asymmetric synthesis. This review attempts to summarise the breadth of use of chiral aziridines in synthesis that has recently been reported. Particular emphasis is put on
the effect of substituents on ring openings, rearrangements and use
as chiral ligands and auxiliaries.
1
2
2.1
2.1.1
2.1.2
2.1.3
2.1.4
2.1.5
2.2
2.3
2.3.1
2.3.2
2.3.3
2.3.4
2.3.5
2.3.6
2.3.7
2.3.8
2.4
2.5
3
3.1
3.2
3.3
4
4.1
4.2
5
5.1
5.2
5.3
5.4
6
7
8
9
Introduction
Stereoselective Ring Opening of Aziridines
Aziridine-2-carboxylates
Hydrogenolysis
Reductive Ring Opening Through Electron Transfer
Heteronucleophile Ring Opening
C-2 Directed Ring Opening
Carbon Nucleophile Ring Opening
Aziridine-2-lactones
Non-carboxylate Aziridines
Reductive Ring Opening
Heteronucleophilic Ring Opening
Aza-Payne Reaction
Carbon Nucleophile Ring Opening
Heteroatom Directed Ring Opening
Ligand Catalysed Asymmetric Ring Opening
Bridged Aziridines
Intramolecular Ring Opening
Aziridine-2-phosphonates
Vinyl Aziridines
Rearrangements and Ring Expansions
N-Acyl Aziridines
Carbonylation Reactions
Cycloadditions
Aziridines as Chiral Ligands and Auxiliaries
Chiral Ligands
Chiral Auxiliaries
Transformations of Aziridine Side Chains
Reactions of Side Chains Attached to Aziridine Carbons
Nitrogen Deprotection
Aziridinyl Anions
Aziridinyl Radicals
Bis-Aziridines
Preparation of Azirines
Aziridinium Ions
Conclusion
Key words: aziridine, asymmetric synthesis, ring opening, rearrangements, regioselectivity
1
Introduction
readily opens with excellent stereo- and regiocontrol to afford a wide variety of more stable ring opened or ring expanded chiral amines. In addition, aziridines can function
as sources of chirality in stereocontrolled reactions and
have found use both as ligands and auxiliaries in asymmetric synthesis.1,2 Since the use of aziridines is ubiquitous in modern organic synthesis, the aim of this review is
to present recent noteworthy applications of chiral aziridines in synthesis to illustrate their breadth of use, rather
than to be completely exhaustive. Particularly, research
conducted since the review by Tanner in 19942 through
1999 shall be presented here. Racemic examples will only
be mentioned if they shed insight into chiral extensions of
the same chemistry. The asymmetric synthesis of aziridines will not be specifically discussed and the reader is
directed to recently published summaries.5−7
2
Chiral aziridines readily undergo regio- and stereoselective ring opening to relieve ring strain allowing access to
amines with predictable α and β stereochemistry. The increasing synthetic accessibility of chiral aziridines5−7 has
propelled their use in ring opening reactions in organic
synthesis. In general, two types of aziridine can be considered: activated and unactivated. The former contain substituents capable of stabilising the developing negative
charge on nitrogen during nucleophilic ring opening. The
latter, also known as simple aziridines are generally unsubstituted or with alkyl substitution on nitrogen and usually require acid catalysis to facilitate ring opening.
2.1
Aziridine-2-carboxylates
Activation of the aziridine nitrogen by an electron-withdrawing group (e.g. acyl, carbamoyl, sulfonyl), by protonation, or by Lewis acids promotes either C-2 attack to
give β-amino acid derivatives or C-3 attack to give α-amino acid derivatives (Scheme 1). Stereoselectivity is generally high and the regioselectivity depends on the ring
substituents, with the majority of nucleophiles reacting at
C-3.
2.1.1
Chiral aziridines have found widespread use in organic
synthesis.1−4 The highly strained three membered ring
Stereoselective Ring Opening of Aziridines
Hydrogenolysis
With C-3 aryl substituted aziridines, hydrogenolysis was
used to regiospecifically cleave the benzylic C−N bond.
Synthesis 2000, No. 10, 1347–1365
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1348
REVIEW
W. McCoull, F. A. Davis
NHR2
Nu
C-2 attack
R1
3
*
*
N
*
*
CO2R3
Nu
CO2R3
2
1
R2
R1
Nu
Nu
C-3 attack
R1 *
*
CO2R3
NHR2
Scheme 1
Such ring opening does not affect the C-2 stereochemistry
of the aziridine which is maintained in the product α-amino acid derivative. Transfer hydrogenation has been used
to open unactivated or sulfonyl activated phenyl aziridine
carboxylates8−12 and phenyl aziridine cyanides.13 It is
noteworthy and uncommon in aziridine chemistry that nitrogen activation was not always necessary. In the case of
geminal disubstituted aziridines the new benzylic stereocentre arises from either inversion or retention of configuration on reduction. The stereoselectivity was substrate
dependent for aziridine esters (2S,3R)-1 and (2R,3S)-4,
but was also influenced by solvent (Scheme 2).11 The retention product always predominated for trisubstituted
aziridine esters 1 with CH2Cl2 giving the best selectivity.
For the tetrasubstituted aziridine esters 4, use of hexane as
solvent with methyl ester gave predominantly the inversion product, while CH2Cl2 gave predominantly the retention product with t-butyl ester. While this behaviour was
not fully understood the affinity of nitrogen for the catalyst in the presence of other chelating functionality and
solvent was proposed to be a factor.
When no benzylic aziridine carbon centre was present,
hydrogenolysis occurred at C-2 for monosubstituted aziridine-2-carboxylate (2R,1’S)-7 to give β-amino ester (S)8. However, the corresponding aziridine alcohol (2R,1’S)9 gave C-3 opening to produce chiral amino alcohol
(2R,1’S)-10.14 Chiral β-amino ester (S)-12 was prepared
using N-tosyl aziridine-2-carboxylate (2S,3S)-11 but the
N-benzyl derivatives could not be used in this C-3 methyl
substituted case as debenzylation proved faster than ring
opening.14 With the trityl group on nitrogen, no reaction
occurred.
Biographical Sketches
Franklin A. Davis was
born in Des Moines, Iowa.
He received his B.S. degree
in 1962 from the University
of Wisconsin and was
awarded a Ph.D. in organic
chemistry from Syracuse
University in 1966 where he
worked with Donald C.
Dittmer. After two years
with Michael J. S. Dewar as
a Welch Postdoctoral Fellow at the University of
Texas he joined the faculty
at Drexel University in
1968. He was the George. S.
Sasin Professor of Chemistry until 1995 when he
joined the Chemistry Department at Temple University. In 1980 he received the
Philadelphia ACS Section
Award and was a Fellow of
the Japan Society for the
Promotion of Sciences in
1992. Dr. Davis is a member
of the executive committees
of the Fluorine and Organic
Divisions of the American
Chemical Society where he
served as Program Chair
(1988−1991) and Chair
(1994) of the Organic Division. His major research interests are in the areas of
asymmetric synthesis and
the development of new
methodologies for stereoselective transformations. In
particular he is interested in
the application of sulfur−nitrogen reagents to the synthesis of bioactive primary
amines; e.g. protein and
nonprotein α- and β-amino
acids, asymmetric oxidations and the regio- and stereoselective fluorination of
organic molecules. Other
interests include natural
product synthesis and heterocyclic chemistry.
William McCoull was born
in Glasgow, Scotland in
1971, received his B.A. in
Chemistry in 1993 and
D.Phil. in 1996, both from
the University of Oxford under the supervision of Prof.
J. E. Baldwin and Dr. R. M.
Adlington. He conducted
postdoctoral studies firstly
with Prof. J. D. Winkler at
the University of Pennsylvania, Philadelphia, USA in
1997 and then with Prof. F.
A. Davis at Temple University, Philadelphia, USA in
1998−1999. Currently, he is
working in the medicinal
chemistry department at AstraZeneca in Cheshire, UK.
His research interests include synthetic methodology, total synthesis and all
aspects of medicinal chemistry.
Synthesis 2000, No. 10, 1347–1365
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1349
Recent Synthetic Applications of Chiral Aziridines
Me
Me
CO2R
H
Me
Ph
N
H
(2S,3R)-1
Ph
Me
Me
CO2R
N
H
(2R,3S)-4
Pd(OH)2
H2, solvent
CO2R
Ph
CO2R
+ Ph
NH2
(2S,3R)-3
inversion
NH2
(2S,3S)-2
retention
88% (86:14)
85% (65:35)
84% (96:4)
90% (79:21)
R = Me (CH2Cl2)
(hexane)
R = t-Bu (CH2Cl2)
(hexane)
97% (67:33)
90% (10:90)
88% (90:10)
95% (40:60)
Me
Me
Pd(OH)2
CO2R
Ph
H2, solvent
R = Me (CH2Cl2)
(hexane)
R = t-Bu (CH2Cl2)
(hexane)
CO2R
+ Ph
Me NH2
(2R,3R)-5
retention
NH2
Me
(2R,3S)-6
inversion
Scheme 2
EtO2C
H
Pd(OH)2
N
H2, AcOH
Me
Ph
(2R,1'S)-7
80%
(phenylsulfonylmethyl)aziridines.17 In the latter two cases, elimination of halide or phenylsulfonyl resulted in an
alkene product.
Ph
EtO2C
N
H
Me
(S)-8
R4
Pd(OH)2
N
HO
HN
60-98%
>95%
R2
R4
CO2Et
R
Scheme 4
H
H
Me
MeO2C
Me
Pd(OH)2
N
H2, EtOH
Tosyl
(2S,3S)-11
80%
H
2.1.3
MeO2C
NHTosyl
(S)-12
Scheme 3
2.1.2
O
14
Ph
Me
(2R,1'S)-10
R3
R1 = Tr, Ts, Boc, Ac,
R2 = OR, NR2, R
3, R4 = alkyl, aryl
H2, EtOH
Me
Ph
(2R,1'S)-9
NR1
SmI2
DMEA
R2
N
R1
13
HO
H
O
R3
Reductive Ring Opening Through Electron
Transfer
Samarium(II) iodide has been used as a reducing agent to
cleave α to the carbonyl of aziridines 13 containing 2acyl, 2-carboxylate or 2-carboxamide functionality to
give β-amino carbonyl compounds 14 in excellent yields
(Scheme 4).15,16 Use of N,N-dimethylethanolamine
(DMEA) as the proton source instead of MeOH or EtOH
was essential to prevent competing nucleophilic ringopening reactions. It was not necessary to activate nitrogen with an electron-withdrawing group and the trityl
group could be used. Although stereochemistry was preserved β to the carbonyl, the stereochemistry at the α position cannot be controlled in this process. Magnesium in
methanol can also be employed as the electron transfer reagent which extended the applicability of this type of reduction to include 2-cyano, 2-halomethyl and 2-
Heteronucleophile Ring Opening
The reaction of heteronucleophiles with aziridine-2-carboxylates generally proceeded at C-3, as exemplified by
the synthesis of the less common α-amino acids (S)-βpyrazolylalanine 16 and (S)-quisqualic acid 17 using nitrogen nucleophiles with Boc activated aziridine (S)-15
(Scheme 5).18
Amine nucleophiles have also been utilised for the asymmetric synthesis of diazepine derivatives19,20 and 2,3-diaminobutanoic acids.21 In the latter case, the aziridine
precursor (1S,2R)-18 was prepared using Sharpless asym-
CO2tBu
H
N
Boc
(S)-15
i. pyrazole
ii. TFA
N
i.1,2,4 oxadiazolidine
-3,5-dione ii. TFA
CO2-
(S)-16
60%
49%
NH3+
N
O
NH3+
N
HN
O
O
CO2-
(S)-17
Scheme 5
Synthesis 2000, No. 10, 1347–1365
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W. McCoull, F. A. Davis
NHCO2Bn
i. H2, Pd/C
CO2tBu ii. TFA
Me
NaN3
CO2H
Me
92%
N3
82%
NHCO2Bn
NH2
NH2
(2R,3R)-19
(2R,3R)-20
CO2tBu
Me
OMs
(1S,2R)-18
80%
t
Me
H
H
BuOK
ButO2C
N
i. TMSN3
NH2
ii. H2, Pd/C
CO2H
iii. TFA
Me
73%
NH2
CO2Bn
(2S,3R)-21
MeOC6H4CH2SH,
BF3•OEt2
Me
CO2Bn
N
H
(R)-23
(2R,3S)-22
MeOC6H4CH2S
78%
CO2Bn
Me
NH2
(S)-24
Scheme 6
metric aminohydroxylation (AA) methodology, which
could be converted directly to (2R,3R)-diaminobutanoic
acid (20) (Scheme 6).21 Alternatively, 18 was cyclised to
aziridine (2S3R)-21 which was in turn ring opened with
azide and reduced to give (2R,3S) diaminobutanoic acid
(22). The versatility of this synthesis was extended in that
the two remaining stereoisomers were prepared analogously by starting with the AA product from the alternative alkene geometric isomer. N-Phthalimidoaziridines
and N−H aziridines reacted cleanly with thiols in the presence of BF3∑OEt2 to give β-thiosubstituted α-amino es-
Ph
H
CO2Me
H
OH
TFA,
45 °C
N
71%
NH2
S
p-Tolyl
O
(SS,2S,3S)-25
Ph
H
CO2Me
Ph
(2S,3R)-26
Me
CO2Me
TFA,
73 °C
N
75%
OH
CO2Me
Ph
Me
S
p-Tolyl
O
(SS,2R,3S)-27
Ph
Me
ters.22,23 Chiral non-racemic α-methylcysteine (S)-24 was
prepared by this method (Scheme 6).24
The introduction of oxygen functionality β to the carboxylate group, as present in substituted serine derivatives,
was achieved using acid promoted ring opening. When
chiral aziridines (SS,2S,3S)-25 and (SS,2R,3S)-27 were
prepared with the sulfinyl group on nitrogen, ring opening
and nitrogen deprotection were performed in one step to
afford β-phenylserine (2S,3R)-26 and the α-methylated
analogue (2R,3R)-28 (Scheme 7).9,10 Alternatively, when
nitrogen was activated with an acetyl group as in
(1’S,2R,3R)-29, deacetylation from both oxygen and nitrogen was necessary after ring opening to afford D-threonine (2R,3S)-30.25
Dicarboxylate aziridines have been reacted with a variety
of nucleophiles (HCl, BnSH, NaN3, TFA, MeOH) to afford β-substituted aspartates (Scheme 8).26 Higher yields
were obtained when the aziridine was activated, particularly with N-methylsulfonyl and regioselectivity was not
an issue with such C2-symmetric aziridines which are
available from enzymatic resolution of racemic material.26
NH2
(2R,3R)-28
MeO2C
H
O
H
CO2Me
N
Me
i. Ac2O, heat
H ii. HCl, MeOH
N
HH
N
OH
Me
72%
CO2H
NH2
SO2Me
(2R,3R)-31
i. NaN3
ii. H2, Pd/C
30%
NH2
MeO2C
CO2Me
NHSO2Me
(2R,3S)-32
Scheme 8
O
(1'S,2R,3R)-29
(2R,3S)-30
Virtually all aziridine ring openings proceed via SN2
mechanism. One notable exception was the TFAA in-
Scheme 7
Synthesis 2000, No. 10, 1347–1365
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REVIEW
Recent Synthetic Applications of Chiral Aziridines
duced ring opening of aziridine (SR,2R,3R)-33.27 Treatment of 33 with aqueous TFA gave the expected SN2 C-3
ring opening to afford L-threo sphingosine precursor
(2R,3S)-34 but TFAA predominantly affords (2R,3R)-35,
a precursor to L-erythro sphingosine with the opposite
chirality of C-3 ring opening (Scheme 9). A [3,3] stereospecific rearrangement of the activated sulfoxide complex 36 was proposed to explain this result.
2.1.4
1351
C-2 Directed Ring Opening
Aromatic functionality can override the general preference for C-3 ring opening. In racemic examples, azirdine
40 incorporated hydroxy functionality at C-2 on treatment
with aqueous TFA and in a useful comparison aziridines
41 and 42 were both treated with NaBH4 and NiCl2 in
MeOH (Scheme 11). The former underwent reduction at
C-3 while the latter was reduced at C-2, i.e. always at the
benzylic position.29
NH2
R
H
H
OH
(2R,3S)-34
72%
CO2Me
CO2tBu
CO2Me
TFA, 0 °C
N Ph
Ns
40
N
R
p-Tolyl
S
59%
O
NHC(O)CF3
R
TFAA, 35 °C
CO2Me
(SR,2R,3R)-33
CO2Et
Ph
CO2Et
N Ph
Ts
42
N
Ts
41
Scheme 11
OH
R = n-C13H27
(2R,3R)-35 (88:12)
R
O
S
CO2Me
+
N
H
O
F3C
p-Tolyl
H
The regiochemistry of ring opening can also be directed
towards C-2 through chelation of the nucleophilic
agent.30,31 Treatment of ester (2R,3S)-43 with LiAlH4 first
reduced the ester to alkoxide 45 which directed the delivery of hydride to open the aziridine at C-2 (Scheme 12).31
After a reoxidation procedure β-amino acids (2R,3S)-44
were obtained.
36
Scheme 9
R
H
Halogen nucleophiles gave ring opening regioselectivity
dependent on the nucleophilic reagent rather than aziridine substrate control (Scheme 10). The conventional C-3
opening proceeded in near quantitative yields for a variety
of C-3-alkyl aziridines (2S,3R)-37 when MgBr2 was used
but with NaBr (or NaI) C-2 opening generally predominated.28 A secondary branch in the alkyl group was necessary for optimal regioselectivity at C-2 and phenyl gave a
1:1 regiochemical mixture under the latter conditions. Removal of the halogen using radical reduction allowed the
preparation of either α- or β-amino acid derivatives.
MgBr2
H
CO2R'
H
R
N
CO2Et
(2S,3R)-37
R
CO2R'
quant.
NHCO2Et
(2R,3S)-38
quant.
NHCO2Et
NaBr
Amberlyst 15
R
CO2R'
Br
(2R,3R)-39
R'= Me, Et
R = Pr, iPr, cyclohexyl, Ph, Me(CH2)11
Scheme 10
i. LiAlH4, 0 °C
ii. NaIO4, RuCl3
N
Ts
(2R,3S)-43
73-86%
H
via
R
NHTs
CO2H
R
Me
(2R,3S)-44
AlH2
Me O
H
R = Et, Ph
N
Ts
45
Scheme 12
2.1.5
Br
Me
CO2Me
Carbon Nucleophile Ring Opening
The use of organometallics to open chiral aziridine-2-carboxylates appears an excellent route for the synthesis of
α-amino acids, but the competing reaction at the ester
functionality is problematic. While organocuprate reagents have obviated this problem, regioselectivity in ring
opening was poor.32 Hydrolysis of the ester to an acid,
then treatment with higher order cuprates overcame this
regioselectivity problem for unsubstituted aziridine (S)-46
(Scheme 13).33 Introduction of a C-3 methyl substituent
caused a lack of selectivity except in the case of the sterically undemanding acetylide nucleophile.33 In accordance
with the expected steric effect of methyl substitution at C2 in aziridine 48, cuprates afford C-3 attack with complete
control of regioselectivity (Scheme 13).34
Synthesis 2000, No. 10, 1347–1365
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1352
REVIEW
W. McCoull, F. A. Davis
CO2H
R2CuCNLi2
H
R = Me 68%
CO2H
R
N
Ts
(S)-46
R =nBu 56%
R =tBu 60%
NHTs
(S)-47
CO2tBu RMgX
Me CuBr•SMe2 R
N
Ts
48
CO2H
Me
R = Ph 57%
2.3.1
R =vinyl 54%
Selective hydrogenolysis at the aziridine benzylic position has been used for the preparation of phenyalanine
derivatives37,38 and in alkaloid synthesis.39 In the absence
of a benzylic aziridine carbon, reductive cleavage of the 2substituted azirdine (2S,1’R,1"S)-53 occurred at the less
hindered C-3 position (Scheme 15).40 2,3-Disubstituted
derivatives (2R,3R,1’R)-55 were also cleaved at C-3 when
either aryl or methyl substituents were attached at this position.38 The presence of (Boc)2O activated the aziridine to
facilitate ring cleavage which occurred prior to removal of
the α-methylbenzyl group.
R = indole 48%
R = iPr 60%
NHTs
R = Ph 52%
49
Scheme 13
2.2
spread use of non-carboxylate containing aziridines for
amino acid synthesis and other purposes.
Aziridine-2-lactones
A comparative study of aziridine-2-carboxylates and aziridine-2-lactones has shown the latter to react with soft nucleophiles at C-2 compared to the general C-3 reactivity
of the former (Scheme 14).35,36 Such regioselectivity was
explained by orbital control where in aziridine-2-lactone
(1S,4S,5R)-50, the calculated LUMO coefficient for C-2
was substantially greater than for C-3. While this is also
true for aziridine-2-carboxylates, the flexible ester side
chain sterically prevents C-2 attack. The nature of the Nactivating group did not affect the regioselectivity. With
hard nucleophiles such as alcohols, charge control directed regioselectivity in both systems to attack at aziridine C3 although lactone opening in 50 preceded aziridine ring
opening and re-lactonization occurred during chromatography to afford (3S,4S,5R)-52.
Reductive Ring Opening
Ph
HO
Pd(OH)2, C, H2,
(Boc)2O
H
N
OH
Me
Ph
85%
NHBoc
Ph
Me
(2S,1'R,1"S)-53
(1S,2S)-54
R
AcO
H
H
N
Pd(OH)2, H2,
(Boc)2O
AcO
67 - 85%
Ph
Me
(2R,3R,1'R)-55
R
NHBoc
(R)-56
R = aryl, Me
Scheme 15
MeO
O
BF3•OEt2,
Soft Nu
MeO
O
R
CbzHN
(3R,4S,5S)-51
O
H
N
Cbz
(1S,4S,5R)-50
O
R =SEt 76%
R = OAc 57%
R = Br 80%
H
MeO
O
BF3•OEt2,
ROH
O
NHCbz
RO
(3S,4S,5R)-52
R =Me 80%
R = Bn 50%
Scheme 14
2.3
Non-carboxylate Aziridines
While the use of aziridine-2-carboxylates appealingly
gives direct access to amino acid derivatives, regioselectivity and chemoselectivity problems have led to wide-
Reductive benzylic centre opening of aziridines has been
achieved using lithium in the presence of catalytic napthalene.41 Activation of nitrogen was not found necessary and
the intermediate dianion was quenched with a variety of
electrophiles to afford amines 59 (Scheme 16). The C-3
aziridine stereocentre was preserved but the benzylic anion derived from (2R,3S)-58 underwent inversion to the
less hindered intermediate derived from (2S,3S)-57 hence
the product stereochemistry β to nitrogen was independent of that in the starting aziridine.
Me
H
H
Ph
N
Me
(2S,3S)-57
OR
Me
Ph
H
H
N
Me
(2R,3S)-58
Scheme 16
Synthesis 2000, No. 10, 1347–1365
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© Thieme Stuttgart · New York
E
i. Li, cat C10H8
ii. E+, H2O
Me
Ph
NHMe
59
52 - 87%
E = H, D, Me2COH,
PrCOH, CH2CH=CH2
c
REVIEW
2.3.2
Recent Synthetic Applications of Chiral Aziridines
Heteronucleophilic Ring Opening
Me
Depending on the nucleophile, Lewis acids or suitable nitrogen activation can be chosen to facilitate aziridine ring
opening. Thiols have been used without Lewis acids or nitrogen activation to react exclusively at a benzylic aziridine centre to produce β-amino thiols.42,43 Introduction of
hydroxy,44 chloro,45 and azide45 functionality was also
performed at the benzylic position in the presence of acid.
Furthermore, unsaturation has also been used to direct regioselective ring opening. Lewis acids facilitate reaction
at the more stable carbocation centre as in the conversion
of aziridine 60 to amino thiol 61 with MeSH and
BF3∑OEt2 (Scheme 17)46 and alkoxy nucleophiles have
been used likewise.47
PhOCO
H
PhOCO
MeSH
BF3•OEt2
H
N
SMe
HN
82%
(CH2)3OCOPh
(CH2)3OCOPh
60
61
Scheme 17
In saturated systems, heteronucleophilic attack generally
proceeded exclusively at the least hindered aziridine carbon. Chiral N-α-methylbenzyl aziridines such as 62 were
easily prepared and ring opened with acetates to provide
amino alcohols 63 (Scheme 18)48 and propane-1,3-diols.49
Imidazole has been used to ring open an N-acylaziridine
with complete control of regioselectivity, but dibenzyl
phosphate was less selective at ambient temperatures.50
F3C
H
N
i. TFA
ii. NaCO3
F3C
OH
NH
BnOH, NaH
TrO
N
Ses
(S)-64
Me
TrO
1353
OBn
NHSes
95%
(S)-65
Scheme 19
oligomer formation and while disubstituted aziridines
gave excellent yields, trisubstituted aziridines gave only
moderate diamine formation.53 When 5 mol% Sn(OTf)2 or
Cu(OTf)2 was used as Lewis acid, only aromatic amines
exhibited aziridine ring opening and an ion complex intermediate was postulated.54 Lewis acids were found unnecessary when methanol was used as solvent and the
reaction proceeded until the amine nucleophile was trialkylated.55,56
2.3.3
Aza-Payne Reaction
The aza-Payne57 rearrangement of aziridine-2-methanols
66 can give rise to two potential intermediates, the oxa-anionic species 68 or the aza-anionic species 69, when treated with base (Scheme 20).58 Intermediate 69 was
predicted computationally and found experimentally to
predominate. Consequently, on reaction with nucleophiles, regioselective attack by pathway d out of the four
possible reaction pathways a−d occurred exclusively to
give amino alcohol 67 in a stereo- and regioselective manner. Higher order cuprate reagents were used to incorporate alkyl, amine and stannyl nucleophiles, and TMSCN
with Lewis acid to incorporate cyanide while thiols were
used without other additives. In the absence of a suitable
activating group on nitrogen, the aza-Payne rearrangement does not occur on formation of an oxo-anionic species.59 When a strong base is not used then direct attack of
the aziridine ring by the external nucleophile (pathway a/
b) has been observed.60
99%
Ph
Me
(2R,1'S)-62
Ph
Me
(2R,1'S)-63
R
H
Amines were found to ring open aziridines in the presence
of 10−20 mol% of Yb(OTf)3 to give 1,2-diamines.53 Protection of the aziridine nitrogen was necessary to avoid
R
H
Scheme 18
An optimised procedure for ring opening of 2,2-disubstituted aziridine (S)-64 used β-trimethylsilylethanesulfonyl
(Ses) as an activating group for nitrogen (Scheme 19).51,52
This gave better regioselectivity for reaction with alkoxides than Lewis acid activation and avoided deacylation
problems caused by other activating groups such as
amides or carbamates. The Ses protecting group was easily removed after elaboration of product (S)-65 using
TBAF. Other nucleophiles including thiols were applicable to this protocol.
OH
OH
Nu
N
Ts
66
NHTs
67
KH
Path d
42 - 99%
a b
R
O
H
i. Nu
ii. H3O+
O
R
H
N
Ts
68
NTs
69 c
d
R (cis or trans) = Me, Ph, CH2OBn
Nu =Me, nBu, PhS, tBuS, CN, SnnBu3, NBn2
Scheme 20
Synthesis 2000, No. 10, 1347–1365
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© Thieme Stuttgart · New York
1354
REVIEW
W. McCoull, F. A. Davis
2.3.4
Carbon Nucleophile Ring Opening
Organocopper reagents are the organometallic reagent of
choice for ring opening of aziridines.30,61−65 Usually lower
order cuprates, derived from organolithium or Grignard
reagents are used as in the preparation of β-arylalanine derivative (2S,3S)-71 (Scheme 21).37 Attack occurred at the
least hindered aziridine carbon unless an additional activation was present such as the benzylic centre in (2S,3R)70. Both organolithium66,67 and Grignard68 reagents have
also been used, but this required robust N-tosyl protection.
Lithium anions derived from 1,3-dithianes have also been
used for the preparation of 2-tosylaminocarbonyl compounds.69
H
R
H
68-80%
OTBS N
Boc
R = Ph,1-naphthyl
(2S,3R)-70
R
Heteroatom Directed Ring Opening
Neighbouring groups have been used to facilitate and direct aziridine ring opening. Acid catalysed methanolysis
of aziridine (1S,6R)-72 gave only (1S,6S)-73 as the regioand stereocontrolled product (Scheme 22).70 Protonation
of the aziridine nitrogen in conformer 75 was stabilized by
an intramolecular hydrogen bond to the endocyclic oxygen thus favouring diaxial attack through this conformer.
OMe
H
N
Ac
(1R,6R)-72
H
H
N
COAr
Ligand Catalysed Asymmetric Ring Opening
10 mol %
cob(I)alamin
H
H
N
Bz
79
H
NHBz
ArSH, Et2Zn
L-(+)-DCHT
81 - 99%
45 - 98% ee
N
AcHN
OMe
(1S,6S)-73
90%
90% ee
(R)-80
H
quan.
HN
SR
O
p-C6H4-NO2
(1S,2S)-82
p-C6H4-NO2
O
81
Ac
N
Ac
O
74
N
85, acetone,
4 MS, -30 °C
H
H
H
N
O
OMe
MeOH
75
Nu
(1R,7S)-78
Ar = p-BnOC6H4
O
MeOH, H+
H
N
Ts
77
TsN
Chiral catalysts have been used to effect asymmetric ring
opening of achiral aziridines.74−78 The ee’s produced varied from poor to excellent and were generally dependent
on the structure of the aziridine, catalyst, solvent and nucleophile. Isomerisation of aziridine 79 using catalytic
cob(I)alamin in MeOH afforded optically active amine
(R)-80 in 90% yield and 90% ee (Scheme 24).74 Aziridine
81 was converted to β-amido thiol (1S,2S)-82 in an opti-
OMe
O
Ph
N
Ts
76a n =1
76b n =2
2.3.6
NHBoc
(2S,3S)-71
Scheme 21
2.3.5
OBn
n
Scheme 23
OTBS Me
Me2CuLi
shown and was not dependent upon the presence of a
Lewis acid or the nature of the aziridine nitrogen activating group.72,73 An electronic effect was used to explain
this behaviour where nucleophilic attack occurs at the carbon with the larger positive charge distribution.
95%
94% ee
N3
83 Ar
OMe
Ar
(1R,2R)-84
Ar = o,p-NO2-C6H3
Scheme 22
Ph
A bridging Lewis acid also explains why AlMe3 facilitated addition of PhC∫CLi to aziridines 76a/b but not to 77
since the latter does not contain a coordinating heteroatom
substituent (Scheme 23).71 In the absence of the AlMe3
there was negligible reaction. The tosylamide nitrogen in
78 directed acid catalysed attack by water to the position
Synthesis 2000, No. 10, 1347–1365
ISSN 0039-7881
Si
N
Cr
O Ph Me
N3
O
(1S,2R)-85
Scheme 24
© Thieme Stuttgart · New York
NH
REVIEW
Recent Synthetic Applications of Chiral Aziridines
mised 98% yield and 93% ee using a crucial 1:3:1:4.8 ratio of 81:Et2Zn:L-(+)-DCHT (dicyclohexyl tartrate):thiol
in toluene.76 Aliphatic thiols gave poor ee’s and the reaction could not be performed with catalytic amounts of zinc
complex. Grignard reagents have also been used with
chiral copper catalysts to desymmetrise N-sulfonylaziridines.77 N-Alkyl substituted aziridine 83 was ring opened
to afford amine (1R,2R)-84 using the tridentate Schiff
base chromium complex 85.78 Unsaturated, acyclic and
five membered cyclic meso aziridines also gave good
yields and enantioselectivities. Amide or carbamate activated aziridines however gave poor enantioselectivites
and sulfonyl activated aziridines were unreactive. In an
interesting comparison of aziridine versus epoxide reactivity in the same molecule, chiral bases were used to desymmetrise an epoxide while leaving a Ndiphenylphosphinyl aziridine intact.79
2.3.7
Bridged Aziridines
N3
H
O
N
R
N
Ph
NHBn
H
H
OBn CN
N
Boc
(2R,3S,4S,5R,6S)-88
N
Ts
(R)-89
O
o-MeBn
N
CO2tBu
a
NHMe
H
H
N
SO2Ph
b
N
Ts a:b = 5:2
(S)-91
(S)-90
Scheme 26
Aziridine-2-phosphonates
Aziridine-2-phosphonates undergo ring-opening reactions analogous to aziridine carboxylates to form α-amino
phosphonate derivatives.86−88 trans-Substituted aziridine
phosphonates were found to be more reactive towards nucleophilic ring opening than their cis counterparts.87 NSulfinyl aziridine (SS,2R,3R)-92 was deprotected and hydrogenolysed as the unactivated aziridine to afford the
first asymmetric synthesis of (R)-α-methylphosphophenylalanine (93) (Scheme 27).86 Furthermore, methanol
was used as a nucleophile to obtain the α,β-trisubstituted
phosphonate derivatives in 90% de and (1R,2S)-94 was
isolated in high yield.
O
R
NaN3
N
N
Ph
O
(7S,1'R)-86a R = Ph
(7S,1'R)-86b R = Pr
O
(7S,1'S)-87a R = Ph, 90%
(7S,1'S)-87b R = Pr, 94%
H
PO3Et2
Me
Ph
i. TFA, 0 °C
ii. HCO2NH4,
Pd/C
70%
Ph
PO3Et2
H2N Me
(R)-93
N
S
p-Tolyl
O
(SS,2R,3R)-92
Scheme 25
2.3.8
Me3Si
OBn OBn
2.4
Bridged aziridines were readily opened by nucleophiles at
the least hindered aziridine carbon.80−82 Regiochemistry
can also be controlled by the electroattracting effect of
heteroatoms. Aziridines 86a and 86b were both ring
opened by azide at the same position to form 87a/b where
neither position is sterically more available (Scheme
25).83 While 86a was directed by the benzylic nature of
one of the aziridine carbons, in 86b the oxazolidinone was
proposed to deactivate the proximal aziridine carbon to
nucleophilic attack.
1355
Intramolecular Ring Opening
72%
BF3•OEt2,
MeOH, 55 °C
H OMe
PO3Et2
Ph
H2N Me
(1R,2S)-94
The regioselectivity of intramolecular aziridine ring openings was strongly affected by the size of the ring formed
and often different from that expected from intermolecular attack. A 6-membered imino sugar was formed from
intramolecular cyclisation at the most hindered aziridine
carbon of (2R,3S,4S,5R,6S)-88 (Scheme 26).84 Intramolecular allylation occurred to form only 6-membered ring
products on treatment of (R)-89 with BF3∑OEt2 and competing chairlike transition states were used to explain
modest diastereoselectivity.61 Likewise, the ester enolate
derived from (S)-90 forms a 5-membered ring with 2:1 ratio of diastereomers.85 In the case of (S)-91, the electron
attracting effect of the second nitrogen may explain why
7 as well as 6 membered ring formation occurred.19
Scheme 27
2.5
Vinyl Aziridines
Vinyl aziridines have been utilised as precursors to (E)alkene isosteres of peptides through reaction with organocopper reagents.89−91 Excellent diastereoselectivity and
high yields were obtained in an anti-SN2’ reaction for Nacyl, peptidyl, carbamoyl and sulfonyl activated aziridines. Both (E)-α,β-enoate 95 and (Z)-α,β-enoate 96 gave
(E)-alkene product (2R,5S,3E)-97 as a result of a predominant reactive conformer dictated by minimizing allylic
1,3 strain with only minor amounts of products arising
from γ-alkylation (Scheme 28).90 The aziridine stereo-
Synthesis 2000, No. 10, 1347–1365
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1356
REVIEW
W. McCoull, F. A. Davis
chemistry in (4R,5S,2Z)-98 was likewise relayed to control the α-stereocentre in (2S,5S,3E)-99. In contrast,
oxygenation at the γ-position using TFA or methanesulfonic acid occurred with stereo- and regioselective SN2
aziridine ring opening of (4R,5S,2E)-100 (Scheme 28).92
The diphenylphosphinyl (Dpp) group has also been used
to activate vinyl aziridines and resulted in exclusive antiSN2’ attack by dialkyl copper lithium and stannyl cuprate
reagents.93 In densely functionalised vinyl aziridine systems, both SN2’ and SN2 behaviour has been observed.94
CO2Me
Me
H
H
N
Ts
(4R,5S,2E)-95
H
Me
H
N
Ts CO2Me
(4S,5S,2Z)-96
H
EtO2C
N
Me
i
95%
i
Me
NHR'
R
CO2Et
CO2Et
H
H
R"CuLn
105
R
H
R
Pd(PPh3)4
H
H
R'
(2R,3S)-107
R = Me, iPr, iBu
R' = Ms, Ts, Mts, Pmc
CO2Me
OR
TFA
or
MSA
Scheme 30
i
Pr
CO2Me
NHMts
(4S,5S,2E)-101 R = H, 93%
(4S,5S,2E)-102 R = Ms, quant.
(Scheme 31).98−101 Aziridine 108 underwent an aza-[2,3]Wittig rearrangement102 to form tetrahydropyridine 109 in
excellent yield99 while 110 afforded lactam 111 in an aza[3,3]-Claisen through transition state 112 (Scheme 31).101
Substitution of the alkene also afforded stereocontrol at
the β-position. The reaction was less successful for N-propargyl vinyl aziridines where competing reaction pathways have been reported.103
Scheme 28
Me
H
The Michael reaction Initiated Ring Closure (MIRC) reaction has been applied to activated vinyl aziridines 103
for the synthesis of cyclopropanes 104 (Scheme 29).95 Addition of Grignard reagents catalysed by CuCN gave the
highest yields and the cis cyclopropane product generally
predominated as explained by allylic strain arguments,
through the preferred reactive conformer 105. Increasing
the bulk of the aziridine substituents generally gave improved cis:trans ratios of up to 80% de.
While cis or trans aziridines are generally prepared independently, in the case of N-alkyl/arylsulfonyl-3-alkyl-2vinylaziridines, palladium(0)-catalysed isomerisation of
trans isomers allowed preparation of their cis-counterparts. In accord with computationally predicted thermodynamic stabilities (2S,3S)-106 was isomerised to
(2R,3S)-107 in ratios generally greater than 95:5 (Scheme
30).96,97
Rearrangement of vinyl aziridines has been used in stereoselective alkaloid and seven-membered lactam synthesis
Synthesis 2000, No. 10, 1347–1365
H
N
N
NHTs
(2S,5S,3E)-99
CO2Me
N
Mts
(4R,5S,2E)-100
R
N R'
R'
(2S,3S)-106
94%
H
EtO2C
104
R = Me, Hex
R' = Ts, Mts
R" = Me, Bu
CO2Me
NHTs
(2R,5S,3E)-97
i. Me2Zn•2LiCl•2LiBr, 20 mol% CuCN
Pri
H
46-97%
H
Me
88%
N
Ts
(4R,5S,2Z)-98
EtO2C
Scheme 29
i
H CO2Me
R
R"MgX
H 10 mol% CuCN
-78 °C
CO2Et R'
103
Me
Me
H
R
ISSN 0039-7881
LDA,
-78 °C
H
N
99%
Me
CO2tBu
108
N
H
109
Hα
H
N
OBn
81%
N
H
OBn
O
Bn
110
H
via
Hβ
Hα
Bn
OBn
N
112
Scheme 31
© Thieme Stuttgart · New York
Hβ
LHMDS,
-78 °C
H
Bn
CO2tBu
OLi
111
O
REVIEW
Recent Synthetic Applications of Chiral Aziridines
acid and R = Me then threonine, D-serine and D-isoserine
containing dipeptides were obtained. Conversion of aziridine 118 to oxazolidinone 119 was facilitated by sodium
iodide and subsequent alkaline hydrolysis resulted in formation of amino alcohol 120.46 Racemic phenylserine 123
was prepared from aziridine 121 by rearrangement to oxazolidinone 122 then alkaline hydrolysis.110 The phenyl
functionality was key to the rearrangement of the Boc
group onto the C-3 aziridine position and methyl or isopropyl substitution at this position afforded poor yields.
Under thermal conditions, vinyl aziridines (2R,3R)-113
underwent homodienyl-[1,5]-hydrogen shifts to give
chiral imines (R)-114 (Scheme 32).104 Substitution of the
alkene in 113 retarded the reaction while the presence of
unsaturation in the R group significantly increased the reaction rate. Accordingly, aza-[2,3]-Wittig precursors such
as 108 or 110 are not stored at room temperature else they
are decomposed via [1,5]-hydrogen shift.
t
H
t
Bu
H
PhH,
reflux
N
Bu
H
The balance of reactivity between direct aziridine ring
opening and rearrangement of acylaziridines has been investigated.111,112 Such reactivity was controlled by judicious choice of "orthogonal" Lewis acids. The oxophilic
Lewis acid Yb(biphenol)OTf was postulated to coordinate to the carbonyl oxygen thus activating the aziridine
124 to external nucleophilic attack forming 125 while the
more azaphilic Lewis acid Cu(OTf)2 was postulated to coordinate to the amide nitrogen thus catalyzing rearrangement to oxazoline 126 (Scheme 34). In the latter case, a
chiral non-racemic example rearranged stereospecifically
with retention of configuration.
N
H
R
(2R,3R)-113
R
(R)-114
R = CO2tBu, CCH, Ph, nHex
Scheme 32
3
Rearrangements and Ring Expansions
3.1
N-Acyl Aziridines
Aziridino cyclopropane 127 underwent rearrangement to
the bicyclic tropane alkaloid skeleton 128 using BF3∑OEt2
(Scheme 35).113 The cyclopropyl carbinyl cation 130 was
initially formed and rearranged to cation 131, which was
trapped by the sulfonamide nitrogen to give 128 or by
fluoride to give 129. When carbamate protection was used
on nitrogen, the reduced nucleophilicity of nitrogen resulted in exclusive fluoride trapping.
Acyl aziridines readily rearrange to oxazolines under thermal, acidic or nucleophilic conditions.105−109 Aziridines
(2R,3S)-115 thermally rearranged to afford oxazolines
(4R,5S)-116 with complete regio- and stereocontrol
(Scheme 33).105−107 Yields were excellent in chloroform
but other solvents gave very slow reactions. Subsequent
mild acid hydrolysis yielded β-hydroxy α-amino acid derivatives (2R,3S)-117 or in the case of R’ being an amino
O
O
R
H
H
R
X
CHCl3
N
O
X
OH
PTSA,
H2O
N
>95%
O
R'
(2R,3S)-115
R
NHCOR'
PhOCO
H
H
N
A
H
N
A
CO2Me
Ph
H
CO2Me
N
Boc
121
O
BF3•OEt2
98%
O
Me
NaOH
95%
O
119
118
A = (CH2)3OCOPh
Ph
H
Ph
HO
H
70%
NMe
R = Me, Et, Pr
R' = Me, Ph
(2R,3S)-117
Boc2O,
NaI
N
X=
X
>90%
R'
(4R,5S)-116
PhOCO
1357
NH
HN
OH
(CH2)3OH
120
LiOH,
H2O
OH
CO2H
Ph
90%
O
122
NH2
123
Scheme 33
Synthesis 2000, No. 10, 1347–1365
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1358
REVIEW
W. McCoull, F. A. Davis
opened then eliminated the organometallic species before
carbonyl insertion could occur. Use of stoichiometric
nonacarbonyldiiron under sonication conditions converted aziridine (5R,6S,3E)-135 to the exo lactam complex (S)-136 (Scheme 36).116 Subsequent reduction of
the ketone functionality with sodium borohydride proceeded stereoselectively and for racemic examples oxidative decomplexation was performed using Me3NO to give
β-lactams such as (3S,4S,1S, 1’E)-137 in 54−69% yield. A
similar ring expansion has also been applied to bicyclic
vinyl aziridines.117
TMSN3,
Yb(biphenol)OTf
N3
84%
H
NHCOR
125
H
N
89%
O
R
Cu(OTf)2
124
O
N
R
126
3.3
Scheme 34
Aziridines can be precursors to azomethine ylides leading
to a wide variety of thermal or photochemical [2+3] cycloaddition reactions. For example five-membered heterocycles have been prepared by reaction of aziridines
with heterocumulenes,118 thiones119 and even C60.120 Intramolecular azomethine cycloadditions have been used
in alkaloid synthesis121 and notably in a computationally
guided design of a silicon based tether system in aziridine
(R)-138 (Scheme 37).122 Photolysis of 138 afforded the
endo-re product (3R,4S,6S,1’R)-139 in 64% yield and
re:si ratio of 16:1. With larger tethers, the transition state
energy calculations favored a switch to endo-si products
as was borne out by experiment.
F
BF3•OEt2
N
Ts
SO2Ph
H
H
N
Ts
127
+
TsHN
SO2Ph
128
45%
SO2Ph
129
30%
F3BNTs
F3BNTs
via
PhO2S
131
PhO2S
130
Cycloadditions
Scheme 35
Me
O
3.2
Ph
Carbonylation Reactions
Aziridines are precursors to β-lactams through carbonylative ring expansion reactions.114 This has been applied to
disubstituted cis aziridine 132 to quantitatively afford the
trans-β-lactam products 133 and 134 in 92:8 ratio using
dicobalt octacarbonyl as catalyst (Scheme 36).115 Likewise, the corresponding trans-aziridine gave β-lactam
products with inversion of stereochemistry. However this
procedure failed with aziridine carboxylates which ring
Me
H
OTBS
H
N
Bn
132
NMe
Co2(CO)8
500 psi CO
100 °C
hν
MeCN
isoprene
N
H
N
O
O
OTBS
NBn
Me
TBSO
+
NBn
O
O
133
134
92 : 8
O
O
Me
H
H
N
Bn
(5R,6S,3E)-135
Fe2(CO)9
sonication
68%
(dr 18:1)
i. NaBH4,
-70 °C, 76%
Fe(CO)3
O
BnN
Me
H
(S)-136
ii. Me3NO,
0 °C, 63%
(racemic example)
Scheme 36
Synthesis 2000, No. 10, 1347–1365
ISSN 0039-7881
© Thieme Stuttgart · New York
Si
Ph
Ph
(3R,4S,6S,1'R)-139
Ph
Scheme 37
Me
100%
Ph
O
O Si
Ph
(R)-138
N
O
O
H
BnN
OH
H
Me H
(3S,4S,3'S,1'E)-137
REVIEW
4
Recent Synthetic Applications of Chiral Aziridines
Aziridines as Chiral Ligands and Auxiliaries
Me
OH
H
4.1
O
Chiral Ligands
The concentrated density of stereochemical information
located close to a good σ-donor nitrogen makes chiral
aziridines attractive ligands for asymmetric catalysis. In
an extension of Corey’s chiral oxazaborolidines for the
enantioselective reduction of prochiral ketones, aziridine
2-carbinols (2S,3R)-140 have been used as precatalysts to
prepare oxazaborolidines (2S,3R)-141 (Scheme 38).123
When used with borane-dimethylsulfide complex for the
reduction of acetophenone to (R)-phenylethyl alcohol,
enantioselectivities were greater than 90%.
N
Ph
PPh2
H
(E)-144
via
1359
H
O
N
Bn
(2S,3S)-145
HN
Et2Zn, 0 °C
Ph
63%
94% ee
PPh2
Et
H
(R)-146
Ph O
Ph
P
Zn Et
O
Et
Zn
N
Me
N
Ph
Ph
H
H
R
H
Ph
Ph
H
R
N
N
H
OH
R = H, Me
B
Et Et
H
N
HO
Scheme 39
O
H
OH
H
147
H
(2S,3R)-141
(2S,3R)-140
Et
Et
Ph
Ph
N
Ph
Ph
OH
Ph
Ph
Ph
(S,S)-142
(S)-143
Scheme 38
A range of aziridine 2-carbinols have been screened as
catalysts for the enantioselective addition of diethylzinc to
aldehydes and aziridine (S,S)-142 gave up to 97% ee and
good yields.124 An equally effective N-trityl aziridine has
been studied and the corresponding polymer supported
catalyst (S)-143 prepared.125,126 High enantioselectivity
was retained and the catalyst was recycled without significant loss in enantioselectivity. Aziridine alcohols have
also been screened as promoters of enantioselective addition of dialkylzincs to N-(diphenylphosphinoyl) imines
such as (E)-144 (Scheme 39).127 Aziridine (2S,3S)-145
gave the best enantioselectivity for formation of amine
(R)-146. The aziridine could be recovered in good yield
(90%) but use of catalytic quantities resulted in a reduced
enantioselectivity. The stereochemical outcome was rationalised by transition state 147 where the C-3 methyl
substituent sterically directs attack of the imino bond from
one face and a favourable π−π interaction accounted for
improved selectivity of N-benzyl over N-alkyl aziridine
promoters. An aziridine carboxylate has also been used as
a ligand for rhodium catalysed cyclopropanation with
modest enantioselectivity.128
C2-Symmetric bis-aziridines have been studied as ligands
in a number of metal mediated asymmetric reactions.129−
132
A two carbon tether between the aziridine nitrogens
was optimal, regardless of the metal used, to allow five
membered chelate formation, and the other aziridine side
chains were varied for steric and electronic requirements.
Bis-aziridine (2S,3S,2’S,3’S)-148 generally showed the
best performance. Osmium mediated asymmetric dihydroxylation of trans-stilbene 149 and palladium catalysed
allylic alkylation of 151 proceeded in excellent yields and
enantioselectivity using 148 (Scheme 40). Copper catalysed cyclopropanation and aziridination of styrene 153
gave poorer ee’s but in the former exchange of the phenyl
for benzyl substituents on ligand 148 increased the ee to
90%. Addition of organolithium reagents to imines such
as 156 gave variable yields and enantioselectivities up to
89%.133
4.2
Chiral Auxiliaries
C2-Symmetric aziridines have been utilised as chiral auxiliaries.2,134 Amide (2S,3S)-158 underwent diastereoselective alkylation when treated with a lithium base then
benzyl bromide (Scheme 41). A side-chain oxygen chelates with the lithium cation of a Z-enolate and the C2symmetry forces the same intermediate if nitrogen inversion occurs. Nonsymmetrical aziridines consequentially
resulted in poorer diastereoselectivity as did aziridines
lacking side-chain oxygens. However, in aldol reactions,
aziridines lacking side-chain oxygens produced better selectivities. Aziridine (2S,3S)-161 afforded only syn-aldol
products 162 and 163 with the former generally predominant as rationalised by a Zimmerman−Traxler transition
state (Scheme 41).
Synthesis 2000, No. 10, 1347–1365
ISSN 0039-7881
© Thieme Stuttgart · New York
1360
REVIEW
W. McCoull, F. A. Davis
H
Ph
H
Ph
Ph H
5
Transformations of Aziridine Side Chains
5.1
Reactions of Side Chains Attached to Aziridine Carbons
H
N
N
Ph
(2S,3S,2'S,3'S)-148
Ph
Ph
OAc
Ph
Ph
151
Ph
Ph
90%
95% ee
(E)-149
OH
(S,S)-150
(π-allyl)Pd2Cl2,
NaCH(CO2Me)2,
148
89%
>99% ee
MeO2C
CO2Me
Ph
Ph
(R)-152
CO2Et
CuOTf,148,
N2CHCO2Et, 0 °C
Ph
153
Ph
(2S,3S)-154
82%
60% ee
CuOTf,148,
PhINTs, 0 °C
NTs
Ph
NAr
MeLi,
148, -78 °C
Ph
Me
H
(R)-157
Ar = p-MeO-C6H4
Scheme 40
H
BnO
H
OBn
H
N
O
Nitrogen Deprotection
Acyl, carbamoyl or sulfinyl protecting groups on aziridines are generally easily removed. However, aziridines
are often prepared or utilised with an arenesulfonyl group
attached to nitrogen which is not as readily removed except under harsh conditions.85,137,138 Samarium iodide has
been used for such a purpose with alkyl substituted
aziridines139 but is not a general method since aziridine
carboxylates will ring open.15,16 Lithium in the presence of
di-tert-butyl biphenyl (DTBB) was found to be of some
application, notably facilitating removal of nosyl functionality from aziridine (S)-172 (Scheme 43).138 Magnesium in methanol under ultrasonic conditions was also
found useful to deprotect aziridine carboxylate (2S,3S)-
NHAr
47%
67% ee
Ph
H
(E)-156
5.2
Ph
(S)-155
68%
33% ee
153
The inherent reactivity of aziridines to nucleophiles limits
the amount of chemistry that can be conducted on aziridine side chains. However aziridine carboxaldehyde
(2S,1’R)-164 is noteworthy in its configurational stability
attributable to ring strain of the aziridine. It was found to
react with a variety of phenyl, naphthyl, furyl and phenanthryl lithium (ArLi) reagents to afford alcohols
(2S,1’R,1"S)-165 in excellent yields and high diastereoselectivities (Scheme 42).40 A diastereoselective dihydroxylation of vinyl aziridine (2R,3S)-166 has been reported
using osmium tetroxide where allylic strain dictated the
preferred reactive conformation (Scheme 42).135 Methylene aziridine (R)-169 underwent [2+2] cycloaddition with
tetracyanoethylene (TCNE) to afford 5-azaspiro[3.2]hexanes (2R,1’R)-170 and (2S,1’R)-171 in up to 68% de
(Scheme 42).136
OH
OsO4,
148, -78 °C
H
OBn
OBn
H
H
i. LiHMDS
ii. BnBr
BnO
88%
Bn
N
N
BnO
+
Bn
O
O
>99 : 1
(2S,3S)-158
nBu
nBu
H
nBu
H
N
O
(2S,3S)-161
i. LiHMDS
ii. RCHO
37-91%
50-98%de
R = alkyl, aryl
nBu
H
n
H
+
O
R
ISSN 0039-7881
nBu
N
N
HO
H
H
Bu
O
HO
R
162
Scheme 41
Synthesis 2000, No. 10, 1347–1365
(2S,3S,2'S)-160
(2S,3S,2'R)-159
© Thieme Stuttgart · New York
163
REVIEW
H H
Ar
O
ArLi, LiCl,
-78 °C
N
Ph
Me
(2S,1'R)-164
iPr
H
H
N
Ts
(2R,3S)-166
OsO4
86%
HO
81-89%
66-94% de
Me
i
H
N
Ph
Me
(2S,1'R,1"S)-165
OH
OH
i
Me
HO
OH
p-Tolyl
i. MeMgX,
t
H
S O
H
R
BuLi, <-70 °C
ii. E+
Ph
Me
Ph
Me
N
N
43 - 96%
Ph
Ph
(2R,3R)-176
177
R = D, CH(OH)Ph, CO2Et, PO3Et2
Pr
Pr
+ H
H
N
N
82 : 18
Ts
Ts
(2S,3S,1'S)-167
(2S,3S,1'R)-168
H
H
O
CN CN
NC
N
CN
TCNE
N
32-82%
+
N
R
OBn
(R)-169
CN
N
N
E
70 - 98%
N
Ph
178
CN
O
i. nBuLi,
-78 °C
ii. E+
H
N
Ph
179
CN
NC
R
R
OBn
(2R,1'R)-170
OBn
(2S,1'R)-171
Scheme 42
E = D, Me, SiMe3,
CH2CH=CH2, Me2COH
O
N
R
N
Ph
180
R = Me, iPr, iBu, Ph
R = Ph, m-Cl-Ph, m-MeO-Ph,
p-MeO-Ph, Me
OH
Scheme 44
174, albeit accompanied by some ring opening.138 Sodium
naphthalenide has recently been reported to deprotect Ntoluenesulfonyl aziridines for a variety of examples.137,140
However, 2-carboxylate substitution led to decomposition
although 2-amide functionality was tolerated.
Me
H
H
Bn
CO2Cy
H
N
N
H (S)-173
5.4
Aziridinyl Radicals
There are few reports of chiral aziridinyl radicals but they
have been generated from bromoaziridines.146,147 Treatment of aziridine epimers 181 with ACCN and Bu3SnH
under high dilution afforded a chiral aziridinyl radical
which cyclised onto the indole functionality (Scheme 45).
Reductive cyclisation predominated in this system to afford 182 and 183 whereas dimerisation occurred when an
electron withdrawing group was attached to the aziridine.
Ts (2S,3S)-174
Ns (S)-172
i, 55%
1361
Recent Synthetic Applications of Chiral Aziridines
ii, 75%
H (2S,3S)-175
OTBS
OBn
i. Li, DTBB, THF, -78 °C
ii. Mg, MeOH, sonication
H
Scheme 43
R
OBn
5.3
NBoc
Aziridinyl Anions
The use of aziridinyl anions has been reviewed although
only a limited number studies have been conducted.141
Recently aziridine borane complexes have been lithiated
and reacted with electrophiles.142,143 In addition, sulfinyl
aziridine (2R,3R)-176 was subjected to sulfoxide-lithium
exchange and quenched with range of electrophiles,
mainly aldehydes and ketones (Scheme 44).144 Oxazolinyl
aziridinyl anions have increased the scope for introducing
substituents directly to the aziridine ring (Scheme 44).145
The aziridinyllithium species was stable at −78 °C and
could be quenched by a variety of electrophiles to give
aziridine 179. Notably, reaction with aldehydes was anti
selective and a range of hydroxy alkyl aziridines 180 were
prepared.
H
N
OTBS
nBu SnH
3
R
N
ACCN
N
Boc
181 (3.8:1)
+
OBn
Br
H
H
182
51%
OTBS
H
R
N
H
NBoc
H
R = CO2Me
183
5%
Scheme 45
Synthesis 2000, No. 10, 1347–1365
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© Thieme Stuttgart · New York
1362
6
REVIEW
W. McCoull, F. A. Davis
Bis-Aziridines
NC
The role of bis-aziridines as chiral ligands has already
been discussed (Section 4.1). In addition, bis-aziridines
have been utilised in ring-opening reactions although
achieving complete chemoselectivity for a specific pathway has seldom been achieved. Commonly, substituted
pyrrolidines can be obtained from intermolecular aziridine ring opening followed by intramolecular 5-exo-tet
aziridine ring opening as in the preparation of
(2R,3R,4R,5S)-185 from (2S,3R,4R,5S)-184 (Scheme
46).148 Use of the guanidinium cation provided a proton
donor which stifled the intramolecular step leading to
double intermolecular ring opening by azide to give bisamino derivative (2S,3R,4R,5S)-186. Benzyl Grignard reagents have also been used to give bis-amino derivatives
in copper catalysed bis-opening reactions of a similar Boc
activated bis-aziridine.149
BnO
10% INBu4,
NaN3 ,65 °C
CbzN
H
N3
OBn
51%
NHCbz
N
Cbz
(2R,3R,4R,5S)-185
CbzHN
N3
H
BocN
65%
H
(2R,5R)-187
N
Boc NHBoc
(2S,5R)-188
NBoc
AcO
AcOH
70%
N
Boc
NHBoc
(3S,6S)-189
Scheme 47
the reaction yield increased dramatically for an N-tosyl
derivative.11 Desilylative elimination of an N-quinazoline
from a chiral aziridine has also been used to prepare azirines.13,153
OBn
NCbz
OBn H
92%
(2S,3R,4R,5S)-184
N3 H2N=C(NH2)2,
60 °C
NaCN,
55 °C
H
H
CO2Me
N
nC
13H27 S
p-Tolyl
O
(SR,2R,3R)-190
nC
i. TMSCl
-95 °C
ii.LDA
13H27
H
CO2Me
iii. H20
N
62%
(R)-191
Scheme 48
OBn
N3
OBn NHCbz
(2S,3R,4R,5S)-186
Scheme 46
Bis-aziridine (2R,5R)-187 was found to be quite reactive
and unstable to prolonged exposure to silica gel.150 Use of
sodium cyanide in an aprotic solvent gave mainly pyrrolidine (2S,5R)-188 with some bis-opened product (15%)
(Scheme 47).150 However with more reactive nucleophiles
bis-opening became more prevalent. Under acid catalysis
bis-aziridine 187 underwent an SN1 ring opening followed
by 6-exo-tet cyclisation to afford piperidine (3S,6S)-189.
Diethylaluminium cyanide has also been found to favour
piperidine formation.151
An alternative azirine preparation from nitrogen unsubstituted aziridines has been conducted using a Swern oxidation procedure. Aziridine-2-carboxylate (2R,3R)-192
afforded only the 2H-azirine product (R)-193 while the
corresponding aziridine-2-phosphonate (2S,3R)-194 afforded both 2H-azirine (S)-196 and 3H-azirine (R)-195
with the latter predominating (Scheme 49).87,154 A greater
acidifing effect on the geminal aziridine proton by the
H
H
CO2Me
Ph
N
H
(2R,3R)-192
DMSO,
(COCl)2
H
Ph
CO2Me
N
(R)-193
60%
then
NEt3
H
PO3Et2
Ph
7
N
(R)-195
62%
Preparation of Azirines
Chiral N-sulfinylaziridine (SR,2R,3R)-190 underwent βelimination of the sulfinyl group when treated with base at
low temperature to afford the antibiotic (R)-dysidazirine
(191) (Scheme 48).152 The rate of deprotonation of both
aziridine protons was proposed to be competitive with
loss of the C-3 proton leading to product while removal of
the C-2 proton leads to decomposition. When the C-2 position is fully substituted, no such competition exists and
Synthesis 2000, No. 10, 1347–1365
ISSN 0039-7881
H
Ph
H
PO3Et2
N
H
(2S,3R)-194
Scheme 49
© Thieme Stuttgart · New York
DMSO,
(COCl)2
then
NEt3
+
Ph
H
PO3Et2
N
(S)-196
15%
REVIEW
phosphonate group compared to the carboxylate group
was used to explain different elimination pathways for the
respective N-sulfonium intermediates.87
i
i
Pri
TfO
H
When there is no activating group on the aziridine nitrogen, reactivity towards nucleophiles can be dramatically
increased through the formation of an aziridinium ion.155−
158
In the simplest sense, protonation of aziridine (R)-197
using an acid catalyst facilitated ring opening by halogen
and chalcogen nucleophiles. N-Alkylation to afford aziridinium ion 198 further increased reactivity such that nitrogen and carbon nucleophiles could also be used (Scheme
50).156 The aziridinium ion 201 could be generated by
heating chloroamine 200 and was reacted with a range of
primary and secondary amines to give α,β-diamino esters
202 with excellent regioselectivity.157
CF3
H
CF3
H
BF4
i
N
Bn
N
Me
(R)-197
Bn
198
Bn
Me
N
ii
56Nu
96% F3C
199
n
Nu = PPh3, H2O, (Bn)MeNH, BuNH2, NaCH(CO2Et)2,
LiCH2COPh
Cl
CO2Et
Ph
N
iii
O
200
CO2Et
Ph
N
O
201
OH
R2N
R
204
Nu
(R,R)-205
R = Bn, allyl, piperidinyl, morpholinyl, pyrrolidinyl
Nu = uracils, imidazoles, amines, amides, amino
esters
i. TMSOTf, -78 °C; ii. Nu
Scheme 51
use of nitrogen activating groups, Lewis acids and formation of aziridinium ions has facilitated greater diversity of
ring opening. Rearrangements of aziridines has allowed
access to β-lactams and alkaloid skeletons. Furthermore,
both chiral ligands and auxiliaries have been derived from
aziridines. The breadth of organic chemistry involving
chiral aziridines has been demonstrated and their use can
only be expected to increase in the future.
Acknowledgement
For our own studies in the area of aziridine-2-carboxylates and aziridine-2-phosphonates we acknowledge the financial support of the
National Science Foundation and the National Institutes of Health.
NR2
CO2Et Ph
Cl
N
O
202
R = H/ nBu, iPr, tBu, Ph, H or-(CH2)4 or (CH2)2NPh(CH2)2
i. MeI, AgBF4 (50%) or Me3OBF4 (97%); ii. Nu,
0 °C; R2NH, 60 °C, K2CO3
Scheme 50
The Payne Rearrangement-Nucleophilic Trapping Procedure (PRNTP) was used to prepare amino alcohols (R,R)205 from chiral epoxides (2S,3R)-203 via the chiral aziridinium ions 204 (Scheme 51).155 A wide variety of amine
nucleophiles were successfully used, notably amino esters
without any loss of stereochemical purity under these conditions.
9
R
NR2
(2S,3R)-203
ii
Pr
44-93%
N
Aziridinium Ions
i
OTMS
Pr
O
8
1363
Recent Synthetic Applications of Chiral Aziridines
Conclusion
The use of chiral aziridines has been widespread in organic synthesis. Their chemistry has been dominated by facile
ring opening with predictable control of regiochemistry
and stereochemistry using a variety of nucleophiles. The
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Article Identifier:
1437-210X,E;2000,0,10,1347,1365,ftx,en;E03800SS.pdf
Synthesis 2000, No. 10, 1347–1365
ISSN 0039-7881
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