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Chiral AziridinesЧTheir Synthesis and Use in Stereoselective Transformations.

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REVIEWS
Chiral Aziridines-Their
Synthesis and Use in Stereoselective Transformations
David Tanner*
~
The preparation of enantiomerically pure
compounds is one of the major areas of
organic chemistry. Much emphasis is
placed on the elaboration of naturally
occurring starting materials and on the
development of techniques for enantioselective transformations of achiral substrates. In this field, chiral aziridines form
an attractive class of compounds, since
they are available in enantiomerically
pure (or highly enriched) form by a variety of procedures and can be used for
asymmetric synthesis in a number of dif-
ferent ways. The chemistry of aziridines
is dominated by ring-opening reactions,
the driving force for which is relief of
ring strain. By suitable choice of substituents on the carbon and nitrogen
atoms, excellent stereo- and regiocontrol
can be attained in ring-opening reactions
with a wide variety of nucleophiles, including organometallic reagents; this
makes chiral aziridines useful as substrates for the synthesis of important biologically active species including alkaloids, amino acids, and B-lactam anti-
biotics. Substrate-controlled diastereoselective synthesis i s also possible by use
of aziridines as removable chiral auxiliuries, while metalation at a ring carbon
atom allows aziridines to be used as chiral reugenfs for asymmetric synthesis.
Chiral bisaziridines can act as ligonds for
transition metals, and applications in
the challenging field of enantioselective
catalysis can be envisioned. Toa'cij~,(he
exclusion of three-membered curbo- u ~ d
heterocjdes ,from thc. arsencd of the organic chemist is inconceivuble.[ll
1. Introduction
2. Synthesis of Chiral Nonracemic Aziridines
Aziridines 1 are saturated three-membered heterocycles containing one nitrogen atom. This class of compounds dates back
to 1888, when Gabriel (unwittingly) syntheU3
R4
sized the parent member.['] Like other three2 2 '
membered rings such as cyclopropanes and
R - T NP
R5
epoxides, aziridines are highly strained.[j]
I
Ring strain renders aziridines susceptible to
U'
the ring-opening reactions that dominate
1
their chemistry and, as shown below, makes
them useful synthetic intermediates that fully deserve a prominent place in the arsenal of the organic chemist.
In view of the long history of aziridine chemistry, it is not
surprising that the literature on the subject is very extensive. For
the interested reader requiring a general introduction, several
excellent discussions are available.[41The present review of chiral
aziridines is thus intended to be representative rather than comprehensive, and the selection of material inevitably reflects the
author's own interests and/or prejudices. The discussion will
deal mainly (but not exclusively) with nonracemic aziridines,
and an attempt will be made to illustrate their great potential
and versatility as chiral substrates, auxiliaries, reagents, and 1i.gands in the field of stereoselective synthesis.
to chiral nonracemic aziridines is availA variety of
able, most of which rely either on the availability of enantiomerically pure starting materials from natural sources (amino acids.
carbohydrates, hydroxy acids) or on asymmetric transformations
of C-C or C - N double bonds. These two general approaches
are discussed below, together with some recent methods
for efficient enantiomer separation and enzymatic transformations.
[*] Dr. D. Tmner
Department of Organic Chemistry
University of Uppsala
Box 531. S-751 21 Uppsala (Sweden)
2.1. Synthesis from Amino Acids
Since the ring closure of 1,2-amino alcohols or suitable derivatives thereofc6] provides a convenient and usually efficient
synthesis of aziridines, it is not surprising that amino acids are
widely used as chiral starting materials. Some representative
examples are shown in Scheme 1.
The first three
can be conducted easily on a
multigram scale with good overall yields. The conditions used
by Wipf and Miller[1o1to cyclize the threonine moiety of the
peptide 2 provided some insight on the factors governing the
steric course of such Mitsunobu-type["] reactions (see also
Scheme 4). The "one-pot'' method developed by the Dutch
group["' for the synthesis of 3 is noteworthy for its simplicity
and efficiency.
REVIEWS
D. Tanner
OBn
CO,H
1) LIAIH,
H
CH3
NH,
2) TsCI, PY
.
CH3
OBn
H
CH,OTs
H
KOH. MeOH
+
-
AmmH
NHTs
72%
2) MsCl
58%
MsO
N,
p h y C O z H
NH,
NaOH. HO
,
TsCI. ElNPr,
96%
1) LiAlH
*
&
P h ~ c o z H
H
I
NP
-6
I
90%
NHTs
0
0
TS
0
H
H20, 100 O C
99Y o
HZN
5
@OH
N
H
Scheme I , Syntheiis of enantioineric;illy piire ariridines from ainino acids.
R n = CH2Ph. Ts = S0,Tol. DIAD = diisopropll aridocarboxylate. Tr = CPh,.
py = pyidine.
M
e
O
q
2.2. Synthesis from Carbohydrates
o
M
e
N
H
By taking advantage of steric, stereoelectronic. and conforinational effects, the regio- and stereoselective manipulation of
the various hydroxyl groups in carbohydrates is possible." 31
Sugar derivatives are thus attractive chiral starting materials for
a wide variety of synthetic purposes, including the preparation
of aziridines; Scheme 2 shows just a
of the inany
possibilities. As is the case for the amino acids, the major drawback to the use of carbohydrates as starting materials is that
usually only one of a given pair of enantiomeric starting compounds is easily or cheaply available. The unusual regiochemistry of the subsequent ring opening['41 of aziridine 4 will be
discussed in Section 4.2. Spiroaziridines such as 5"'' are very
useful intermediates in the synthesis of important branchedchain amino sugars (Section 5.2). and the chiral bisaziridines
6'18] provide an elegant route to a-amino acids and aldehydes
N3
t:
I
6
Me
Scheme 2 Synthesis ot'enantioinericall~pure aziridinea from carbohydrates. Ms =
S02Me.
(Section 5.3). Further references to the ring closure of azido
alcohols to aziridines by use of organophosphorus reagents can
be found in references [19-211.
David Tanner was horn in 1955 iii Inverness. Scotlrmd, cmd studied cliernisfrj,at thP Univrrsitji
of' Edinhurgli ( B . Sc. 1977) . He then moved to Giitehor<q,Sweden, l lie re he obtciined his
doctorate in 1981 under thr .suprr on of0. Wennwvtrri'ni.After a one-year postdoctoral stay
with K. C. Nicoluou at the Universitj, of' Pennsj,hvnia, he returned to Ciitchwg in 1983 to
pursui' independent research; he rcwived the title of "Docent" ,froin Chabners Utiiversitj~of'
Technologj, in 1986. In 1988 he ,\us appointed t o a Iec~tureship(it the Universitj. of Uppsalu,
kchere he al.so currentljs hol~isa personcil research position in orgcinic sjxthesis mi*ardedbj, the
Swedish Natural Science Re.vecirc.11 Council.
L
REVIEWS
Chiral Ariridines
2.4. Synthesis from Alkenes via Chiral Epoxides
and 1.2-Diols
2.3. Synthesis from Hydroxy Acids
The hydroxy acid most familiar to organic chemists is no doubt
tartaric acid, derivatives of which are not only of great historical
but also allow access to an impressive variety of
enantiomerically pure "building blocks" for synthesis.[z31Tartaric acid is also used to provide the chiral environment for the
Sharpless asymmetric epoxidation reaction discussed in the next
section. Both enantiomers of tartaric acid are readily available
and can be converted to the enantiomerically pure pairs of
aziridines 9 and lo.["' and 11 and 12["] shown in Scheme 3.
Some applications of these C2-symmetric compounds in asymmetric synthesis will be demonstrated in Sections 4.4 and 6.
As emphasized in Schemes 3 and 3, ring opening of epoxides by
nitrogen nucleophiles followed by ring closure of the resultant
1 -2-amino alcohol derivatives is an attractive route to aziridines.
Although epoxides had long been regarded as versatile intermediates and had been used extensively in synthesis,["'] their potential was increased enormously in the 1980s by the discovery of thc
asymmetric epoxidation (AE) reaction of allylic alcohols by
Sharpless et al.[301.This epoxidation is mediated by a titanium(1v)
alkoxide and rut-butyl hydroperoxide in the presence of ;I tartrate ester. As outlined in Scheme 5, this catalytic asymmetric
synthesis provides a general route to all possible stereoisomers
of a given hydroxymethylaziridine (-'2.3-aziridino alcohol").
9
Ts
d
,(+) -tartrate.
"id'l
11
.pi
OH
--c '
Y
O
H
N
R
Scheme .; Synthesis 0 1 C'-synimetric aziridines from tartaric acid. a ) PPh,. dicthyl
a ~ n d i c ~ ~ i - h ~ \ ) l i i ~ e ( Dh)
EA
1. D
N )a:N , . 2. M K I . 3 LiAIH,. R = Et. CH,Ph. Compound 7 :itid the precursor of I I uerc obtained from (+)-tartnric acid. compound
[tic pi-ccurwr o f 12 from tar tartar^ acid.
8
The Mitsunobu-type reactions used for the ring closure[2h1of
the hydroxy sulfonamides 7 and 8 are stereospecific and occur
with inversion at the carbon center bearing the OH group. The
results of the related reactions shown in Scheme 4 can be compared[':- I' and contrasted"'] with that shown for cyclization
o f 2 in Scheme I .
0
a"'/
%..,
HNKAr
C,H,
PPh DEAD
3.
73%
+Me
Ar
OH
,.."Me
One of the many advantages associated with the Sharpless AE
reaction is that both enantiomers of the product are available
equally easily from a common starting material. As pointed out
above. azide ion is often an excellent nucleophile for the ring
opening of epoxides, and azido alcohols can then be converted
to aziridines: the overall epoxide + aziridine transformation is
thus stereospecific (inversion at both carbon atoms of the original
epoxide). Some examples[3 321 are shown in Scheme 6. Aziridino alcohols and esters such as 13 and 14 are very useful chiral
intermediates (see Sections 4.3 and 4.4).
'.
T7.
C5H11
Scheme 5. A general route to chiral 2.3-aztrtdino alcohols hy thc Sh;irple\\ a s y n
metric epoxidation (AE).
Lo
Z
~
I
N
PPh,. DEAD
54%
ArHN
0
regioisomer
R = SirBuMea
Scheme -1. Some alei-eospucific intramolecular Mitsunoho reactions. Ar
Z = hen/!lo.;?ciii-bon\.l.
=
aryl.
Scheme 6 . Synthesis of chiral. nonraccmic ariridino ;ilcohols and esters
ides available by the Sharpless AE reaction.
kiii
cpox-
60 1
D. Tanner
REVIEWS
It is usually of little consequence that the ring-opening reactions shown in Scheme 6 are not regioselective. since both regioisomers of a given azido alcohol eventually yield the same
aziridine. However, in the case of epoxy alcohols, the sequence
does entail teinporary protection of the primary hydroxyl
group. Regioselectivity in the ring opening by a ~ i d e [ ~ ~and
-~’]
secondary’”] or primary[371amines is possible if the reaction is
mediated by aluminum or titanium complexes. The products
from the primary amines have been converted[”I to aziridines
(Scheme 7). Good to excellent regioselectivity in the C-3 ring
The epoxide -+aziridine transformations outlined in Schemes
6-8 involve overall inversion of configuration. However, an
interesting method for conversion of a terminal epoxide to the
corresponding N-tosyl aziridine with overall retention[451was
introduced recently (Scheme 9). This use of sulfur chemistry
OH
N.
Scheme 9. Conversion of a terminal epoxide to an h-tosyl aziridine with retention
of configuration
BnO
Ti(0iPr)Z(N3)Z
85%
W
O
Me
Me
Ti(QPr),, EtzNH
90%
A
O
.
NEtz
O
H
-
OH
H
Ti(O;F‘r).,
H
OH
OH
I
Ph2CHNH
Ph,CHNH,
+
O
-H
70%
OH
(94: 6)
Ph,CHNH
I,
MsCl NEI,
CHPh,
,..+’,”
nicely complements the methods that proceed with overall inversion and thus allows the synthesis of both enantioniers of a
given terminal aziridine from a single chiral epoxide.
While the Sharpless AE reaction is a beautiful example of
catalytic asymmetric synthesis, its major limitation is that the
substrate must contain a “handle” in the form of an allylic
hydroxyl goup. Chiral termind epoxides such as those shown in
Scheme 9 are thus not available directly by the AE method, and
indeed the direct asymmetric epoxidation of “nonfunctionalized”
olefins remains a major challenge.1461However. Sharpless et al.
have provided a very attractive indirect solution to this problem
which relies on cyclic sulfates of chiral 1,2-diols. These compounds are now easily available in enantiomerically pure (or highly enriched) form by the osmium-catalyzed asymmetric dihydroxylation (AD) reaction[47]shown in Scheme 10; the chiral ligands
-OMS
Scheme 7. Regioselective ring opening of epoxy alcohols.
opening of 2,3-epoxy acids and amides by amines[”] and the
C-2 ring opening of 2,3-epoxy esters by azidef401has also been
demonstrated.
A useful tactic in epoxy alcohol chemistry is use of the Payne
rearrangement.[411As shown in Scheme 8, amino epoxides can
perform in an analogous pdshion in the presence of complexes of
titanium[421or aluminum.[431N-Tosylamino epoxides undergo
the same type of rearrangement simply upon treatment with
base (Scheme 8) .[441
16
15’
R
1) LiN,
2) LiAIH,
H
HZN 0
Ph &OH
Ti(OiPr),
63%
OH
*
Ph
A
Scheme 10. Sharpless asymmetric dihydroxylation (AD) as a route to chiral, nonracemic aziridines. The mixtures of reagents used here are denoted AD-mix-a and
AD-mix+.
&OH
H
Scheme 8. Chiral ariridines hy Payne-type rearrangement of amino epoxides
602
in the AD-mix reagents are based on hydroquinidine and hydroquinine. The cyclic sulfates 16 in many ways surpass the
corresponding epoxides in terms of reactivity (“like epoxides
only more reactive”[481).and aziridines are readily available[4y1
from these intermediates. The cyclic sulfites 15 can also be used
for aziridine f ~ r m a t i o n . [ ~ ~ l
Angat
Cheni Inl Ed Engl 1994, 33, 599-619
REVIEWS
Chiral Aziridines
Although the two types of ligands employed in the AD-mix
forinul~ttionsl~']
are not enantiomers, they actually behave as if
they wcre. and the process provides equally easy access to both
enantiomers of ii given 1,2-diol from the same olefin. I n connection with the A D reaction. i t may be mentioned here that osmium also mediates the stereospecific oxyamination of olefins and
thus provides another stereospecific synthesis of a ~ i r i d i n e s . ' ~ ' ]
However. no ennntioselective version of this reaction has yet
been reported.
(x)-(+)-lfI
Pb(OAc),
69%
+
tie
Schemc 11. As!.nimecric synthesi? 01 ariridincs by re;+renl control
2.5. Other Asymmetric Transformations of C-C
Double Bonds
Some of the well-established methods['] for the synthesis of
aziridines from olefins are: 1) addition of IN, or INCO followed
by reductive or hydrolytic ring closure; 2) 1,3-dipolar cycloaddition of azides followed by decomposition of the intermediate
triazoles: 3) addition o f a primary amine to a suitably 2-substituted acrylic acid derivative or Michael addition of a nitrogen
nucleophile followed by expulsion of a leaving group at nitrogen:
and 4) direct addition of nitrene species. These general methods
for aziridine formation can be used to exemplify the "hierarchy"
of asymmetric synthesis. which ranges from substrate control.
through reagent control. to enantioselective catalysis.
Some exanip1esrs2 -"I
of substrate control are presented in
Scheme I I . Although the starting material for the synthesis of
complete in the nitrene r e a c t i o t ~ [ ' ~of
. ~alkene
~'
20. Reagent 21
has not yet been prepared in enantiomerically pure form, but
some asymmetric induction has been claimed["I for an interesting variant of this reaction, in which an optically active oxidant
(lead tetra-(S)-2-methylbutanoate) was used.
In the previously mentioned "hierarchy" of asymmetric synthesis. enantioselective catalysis is at the very top. Two examples
(the Sharpless AE and A D reactions. Section 2.4) have already
been discussed. and three very exciting developments in catalytic
asymmetric a ~ i r i d i n a t i o n [ ' ~ -are
~ ~ ]shown in Scheme 13. For
.Pht7
C0,Ph
-CO,Ph
N
CuoTf
Ph
PhlkNTs
ligand A
'\
I
Ts
97%
64%
-
PI
CuOTf, Phl=NTs
ph-,+
N
I
91 Yo
2-cholestene
Ts
88% ee
0
&e
oMe
oMe ca 100%
+
80%
regioisomer
COCH,
CuOTf, Phl=NTs
NC
COCH,
ligand C
.
NC
\
Ts
75%
- JH
298% eP
Ph
Ph
chiral ligand A
17
I
Schcmc 1 1 . Asyiiiiiietric synrhesis of;iziridine\ by subsiratc control
chiral ligand B
cg
/ \
\ /
-
17'''1 was racemic, optically pure 2-cyclohexen-1-01 is available.ls61 Good to excellent diastereoselectivity in the addition of
nitrenes to chiral enoates has been described by the Dreiding
Scheme 13. Asymmetric
Two examples of reagent control are given in Scheme 12. The
chiral sultiinide reagent
yields aziridine 19 with only modest
enantioselectivity (30 '4 w), whereas asymmetric induction is
related work on the direct (nonenantioselective) aziridination of
alkenes, including catalysis by metalated porphyrins, see references [65 -701.
chiral ligand C
synthesis of ariridines by cnantioselective catalysis
603
D. Tanner
REVlRlVS
This section concludes with the two interesting aziridination
reactions depicted in Scheme 14. The highly diastereo- and
cnantioselective functionalization'"' of all four carbon atoms in
0
I1
Ph I S
-
ATs
284%
CH,
t-/
I lalo
1) NaH, DMSO
2) PhCH=NPh
12'90
Ph
23
ee
Ph
0
0-
N H HCI
>96% P P
-<""'
CN
hv
H,O,a-CD
*
Scheme 10 Reagent control i n the asqmmetric transform;iilon of B C - N double
bond. DMSO = dimethyl sulfbxide. LDA = lithium diisopropqlamidc.
1
NI
CN
26 - 36%
re
Schctiic 11. Cliirnl mi-idinea bq ii\)nimetric cqcloadditioii with
(top) and hq en;intiotclecti\e photocqcliration (bottom).
:I
chiral auxiliarq
the diene u n i t of cyclohexadiene relied on the use of a chiral
auxiliary derived from a carbohydrate.[721The enantioselective
pho t ocycliza ti on reaction in the presence of r-cyclodex t ri n
( Y - C D ) ' ~was
~ ' performed in connection with studies of compounds of potential interest to prebiotic chemistry.
Scheme 17 shows two analogues of the Darzens reaction.[771
For the first.[781which is highly diastereoselective, the authors
suggested a cyclic transition state to explain the observed cis
selectivity. They also pointed out that this type of reaction should
be amenable to the preparation of nonracemic aziridines. The
second example.[791in which a chiral auxiliary is used. shows
that this is indeed the case. It is remarkable that complete
"stereodivergence" is possible here simply by switching the
metal counrerion of the enolate from lithium to zinc!
H
2.6. Asymmetric Transformations of C-N Double Bonds
Aziridines are available by reaction of 2-hydroxy oximes with
Grignard reagents via azirine intermediates (Scheme 15). The
*--
vH
N.
SiMe,
+
)=(OM
CI
OR
26
R = rBu
NI
52%
H
(racemic)
OH
OH
PhMgBr
+M~
PhMgBr
toluene
NOH
N
22
(racemic)
Ar
HO dMe
H
.
Ph
. . I
Scheme 17. Synthesis of cliiral a~iIidineaby Darrens-type i-eiictioiis. M
in
26: L I .
I
H
(racemic)
results of an interesting study"" on the diastereofacial selectivity
of this reaction wcrc interpreted in terms of complexation of the
Grignard reagent t o the alcohol function of 22 followed by
intramolecular delivery of the nucleophile to the less hindered
face of the C-N double bond.
Two cxamplcs of rcagcnt control arc presented i n Scheme 16.
In the lirst, an ,Y-tosylsulfoxiniiner7"' was used as a chiral nucleophilic alkylidene transfer reagent: unfortunately, the enantionieric purity of aziridine 23 was not determined. The second
exainple[7"1shows ii v e ~ yefficient asymmetric synthesis based
on the chemistry of chiral sulfosides in which a stereospecific
desulfinylation reaction of 24 gives aziridine 25. The proposed
intermediate is a chiral metalated aziridine. an interesting type of
nucleophilic species which is discussed in more detail in Section 7.
604
2.7. Chiral Aziridines by Resolution of Racemates
Early
at direct optical resolution of chiral aziridines were not promising. But recently Mori and Toda["] reported an efficient method based on the formation of inclusion
complexes between certain aziridines and the optically active
host compounds 28 and 29, which are derived from tartaric
acid. Enantiomeric purities up to 100% were obtained
(Scheme 18).
An important structural feature of aziridines is the high barrier[821to pyramidal inversion at the ring nitrogen atom when it is
bonded to alkyl or aryl groups or, especially. to heteroatornic
moieties such as CI, OR, or N H 2 , This has allowed the separation[831of the enantioniers (invertomers) of. for example, 1chloro-2.2-dimethylaziridine (30. Scheme 18) by complexation
gas chromatography. This elegant study also allowed accurate
determination of the inversion barrier. which earlier had been
estimated['"] from ' H N M R spectroscopic data.
Chiral Aziridines
0
P h F , 6 P h
Ph
OH
REVIEWS
reaction yielding aziridine 31 in Scheme 19. Enzymes were also
employedLS7]
in the preparation (by selective hydrolysis) of aziridine 32, which is chiral solely because of slow nitrogen inversion.
Wong et a1.[881
prepared the enantiomerically pure aziridines 34
and 35 by enantioselective hydrolysis of 33, and Effenberger
et al.[89,901 have reported the synthesis of enantiomerically pure
aziridine 36 by a sequence involving enzyme-catalyzed cyanohydrin formation.
28 n = O
29 n = l
Ph
HO
ij
complex
L
3. Stereoselective Transformations at Ring Atoms
and in Side Chains without Ring Opening
100% ee
racemic
20% yield
As will be discussed in Section 4, ring opening occurs in many
of the reactions of aziridines. However, for “nonactivated“ aziridines (see Section 4) it is possible to perform stereoselective transformations either at ring atoms (carbon or nitrogen) or in side
chains without disrupting the ring. Some examples are shown in
Schemes 20 and 21.
Me
Me
dMe
N
N
I
CI
($-N
Scheme 1X. Two methods for the resolution of racemic aziridineh
2.8. Enzymatic Routes to Chiral Aziridines
NaOEt
82%
I
I
Ph
Ph
In recent years the use of enzymes in synthetic organic chemistry has increased steadily.[85]A popular technique is the enantioselective hydrolysis of me w diesters. exemplified[86’by the
37
CiAIH,
89%
Ph
Ph
Z
Z
38
,
.
CO,CH,
,!-C02CH3
COZCH3
27%
I
+
1
CI
CI
N&OEt
LP-80-lipase
.
1
+
OEt
0
N
CE
C02Me
6
41 (X=Br)
N
Ph
42 (29% ee)
H
OEt
> 98%
+
Ph
61
41 (X=CI)
+
N-oE~
OEt
> 98% ec
80 - 90%
+
H
40
CAc
OH
39
chiral solvating
agent
I
CI
32 (76%ee)
N+OEI
T-?ph
N
N
[ = N - N ~
Ph
CO,CH,
Rhfzopus delemar
N
33
C02H
-
GI-~3
+
L N - L i
31 (98% ee)
CH,CIz
94%
.
H
2
N
Co2Me
I
H
43 (100%EL)
Scheme 20. Stereoselective transformations at ring atoms of aziridines
99%
ee
n
36
Scheme lr). The use of enzymes in the synthesis ofenanttomerically pure aziridines.
The first examples of Facile nucleophilic displacements at the
carbon atoms in three-membered rings were provided by Deyrup
and Greenwald,[’’] who showed that the products of displacement reactions on 37 and 38 were formed with clean inversion.
As far as the present author is aware, no nonracemic derivatives
of the interesting 1,l‘-diaziridine 39[921have been reported. Attempted asymmetric chlorination at the nitrogen atom in 40 in the
presence of a chiral solvating agent gave 42 with only modest
605
REVIEWS
e n a n t i o ~ e l e c t i v i t y . However,
[~~~
N-brominati~n'"~of optically
pure 43 was completely stereoselective (Scheme 20).
The reactions depicted in Scheme 21 show that aziridines with
suitable substituents on the nitrogen atom may react with powerful nucleophiles such as metal h y d r i d e ~961
~ ~without
~,
ring
.k
..''
LiAIH,(R= Me)
R
or
\/"
N
I
Zn(BH,),
(R = Ph)
aziridines has increased s character as compared to other
aliphatic secondary amines, which results in lower basicity and
reduced rc-donor ability.['021)
If aziridines, whether activated or not, are to be of use in
synthesis, it is of prime importance to be able to control the
stereochemistry and the regiochemistry of the ring-opening process. The issues of stereo- and regioselectivity will be emphasized
in the following discussion, which will deal mainly with activated aziridines.
. J---(rB"'
''.M,+''
IBU
44 (R = Me, Ph)
4.1. Acid-Catalyzed Ring Opening
45
'
The detailed mechanism of acid-catalyzed ring-opening reactions of aziridines has been the subject of much debate.[lo3]Some
examples for both nonactivated and activated aziridines are
shown in Scheme 22. Wade['041interpreted the formation of 50
and 52 from 49 and 51, respectively, in terms of an S1, mechanism (see, however, ref. [105]). Acetolysis of 53 and 54 was proposed['061to occur by an A-2 pathway, in which the acetoxy
group preferentially attacks the carbon atom best able to ac-
'N'
1
rBu
rBu
(98 2, R = Me)
(100 0 R = Ph)
Ph
46
I
n
Scheme 21. Stereoselective transformations in side chains of aziridines
49
opening. Pierre et al.[y71and Laurent et al.[981both explained the results of reduction of 44 by LiAIH, or
Zn(BH,), by the intermediacy of chelate 45. Modest
diastereoselectivity was also observed in the reaction of
aziridino aldehydes with Grignard reagents.[991 The
aminolysis that yields 46 is completely diastereoselective." 1''
H
51
Ph
52
b
AcOH
N
-iG?
Ph
I
As a consequence of the ring strain present in aziridines and related three-membered rings, ring-opening
reactions are a dominant feature of their chemistry.
In this respect, aziridines can be divided into two main
groups,['o11according to the nature of the substituent
on nitrogen. The first group, "nonactivated" aziridines, 47. con.i7
tain a basic niN
N
trogen
atom,
I
I
R
G
and ring-open48
47
ing
reactions
"nonactivated'
"activated"
R = H. alkyl. aryl
G = COR. CO,R, SO,R
usually
occur
only after protonation, quaternization, or formation of a Lewis acid
adduct. The second group, "activated" aziridines, 48,
contain a substituent which can conjugatively stabilize
the negative charge that develops on the nitrogen atom
in the transition state for ring opening by a nucleophile.
(It may also be noted here that the nitrogen lone pair in
H
C02Et
4. Ring-Opening Reactions
53
:Bu 02C,
v
I
OAc
SU0,C
\
5rBuOpC+/ H
HNC02E1
h
w
P
N
I
S0,Ph
55
OAc
/
HNC0,EI
(13 87)
54
p
\
H+-
+
C02Et
v
606
HNC0,Et
h
MeOH, HzSO,
88%
.
ph+H
,o:
e : *hp
PhS0,NH
PhS0,NH
(98: 2)
Scheme 22. Acid-cavdlyzed ring opening of aziridines.
A n R m C h m In/ Ed €ng/ 1994, 33, 599-619
REVIEWS
Chiral Aziridines
commodate some carbenium ion character. Borderline behavior
was observed['07] for the alcoholysis of cu-aziridine 55, which
was cleaved completely regioselectively with nearly complete
inversion (98 :2 ratio of diastereoisomers). Finally, the completely stereo- and regioselective conversion of 56 to 57 provides
an interesting and unusual example of neighboring group participation of benzyl ethers.['081
and the sugar aziridine 62 gave predominantly the product of
diaxial ring opening."
Some "abnormal" nucleophilic ring openings are presented in
Scheme 24. Stamm et a1.["6' ' I 7 ] have explained the unusual
ring opening of 63 both as a single electron transfer process and
also as a borderline S,2 reaction, depending on the nucleophile
used. The anti-Furst-Plattner ring opening that yields @ [ I 4 ] is
more difficult to
4.2. Nucleophilic Ring Opening of Activated Aziridines
The reaction mechanism for the nucleophilic ring opening['091
of activated aziridines is more clear-cut than that for nonactivated
species. and some generalizations can be made. For monocyclic
aziridines. nucleophilic attack is expected to occur by an SN2like mechanism with inversion. Monosubstituted aziridines are
expected to be attacked predominantly or exclusively at the methylene carbon atom. In analogy with epoxides, fused bicyclic aziridines may be expected to obey the Furst-Plattner rule["01 for
zrms-diaxial ring opening. Scheme 23 shows some examples of
"normal" nucleophilic ring-opening reactions. The &/trans isomers 58 and 59 underwent a clean SN2reaction["'] with complete Walden inversion ; the monosubstituted aziridines 60 and
61 were attacked exclusively["2-"4] at the less hindered site;
Mh
N
Me
I
COPh
H
M e b N C O P h
90%
63
63
+
PhSe
------b
M
+
A
M
HNCoPh
major
e
V
P
h
PhCONH
minor
OBn
I
OVoBn
tlnu
-
64
Scheme 24. Some "abnormal" nucleophilic ring-opening reactions
SPh
,,YPh
PhSNa
N
100%
I
&O,Ph
58
H
Ph
PhS0,NH
-
Since organometallic reagents offer a host of possibilities for
selective carbon-carbon bond formation. often under mild reaction conditions, the ring opening of chiral three-membered
heterocycles by organometallic compounds should be an attractive tactic in stereoselective synthesis. While such reactions of
epoxides were quite well explored at a relatively early stage,['201
the corresponding aziridine chemistry developed more slowly.
The difficulties associated with the use of aziridines stem mainly
from the inherently low reactivity of the unactivated heterocycles
and the ambident nature of activated species such as aziridinecarbamates and N-acylaziridines. Some of the problems and
solutions are depicted in Scheme 25.
The work of Hassner and Kascheres['"] on aziridinecarbamate 65 clearly demonstrates the ambident electrophilic nature of
the Substrate. In addition to the convenient synthesis of ketones
shown, N-acylaziridines such as 66["*] provide a route to aldeh y d e ~ . [ ' The
~ ~ ' study conducted by Kozikowski et al.[1241on the
ring opening of 67 and 68 underscores the chemoselectivity of
cuprate reagents and also the greater activating power of the
sulfonyl group relative to the acyl and alkoxycarbonyl groups.
The compatability of cuprates with certain Lewis acids allows
smooth ring opening of the unactivated aziridine 69 under very
mild conditions." 2 5 1 Reactions of more elaborate aziridines with
organometallic reagents are discussed in Sections 4.3 -4.5 and 5.4.
Ph
Ph
SPh
d ; h H
PhSNa
95%
PhS0,NH
I
SO2Ph
59
phy
0
Nafi!-Me
N
OEt
TsNH
TS
60
c Me,SiCN
+
60
II
90%
OEt
I
0
'TMe
H
Ph+cN
Yb(CN),
04%
TsNH
&
+
N
I
Ts
61
P
h 0 .q4
,
O
5. 3
N
b.-.ma OMe ___)
NH,C,
Ph
NaN,
':G..,tc
OMe
PhCONH
N3
(74:*q
Ph AO
62
Scheme 23. Nucleophilic ring opening of activated azindines.
An,qm CAm7 Int Ed Engl 1994, 33, 599-619
.l.llOMe
+
N,
4.3. Ring Opening of Aziridino Alcohols
iNCOPh
Thanks to the experimental simplicity and excellent enantioselectivity of the Sharpless asymmetric epoxidation, 2,3-epoxy alcohols have rapidly gained importance in stereoselective synthesis.
607
REVIEWS
T7
N
D. Tanner
Ph CLi
3
I
85%
ph3c\
HNC0,Et
CO,Et
Ts
71
71'
65
+
65
RLi
-----+
80%
71(71')
R=rBu
.
6
Ho
OR
HNTs
H3cb
N
I
/woR
R ' y
R
95%
RLi
Ts
72
72'
R=CH,Ph
R = SirBuMep
74
73
(R' = H, Me)
R
Ph
H
R = nBu
COPh
66
R
OR
OR
75
76
Scheme 26. Possible regloisomers from the ring opening of
alcohols.
/ r ~ i i . and
\
(,i\ uiridino
C0,Et
67
Dr.
68
T7
N
LiPh,Cu.
I
BF,~OEt,
92%
En
LiAIH,, and DTBAL (diisobutylaluminum hydride) are shown
in Table 1. Excellent C-2 regioselectivity was observed in the
reactions with Red-Al (entries 1 and 2); none of the products of
ring opening at C-3 could be detected by high-field ' H N M R
spectroscopy. Since the corresponding epoxy alcohols'' 2 8 ' 301
behave in the same way. it seems reasonable to suggest that the
free hydroxyl group first coordinates to the reagent. which thus
allows intramolecular delivery of the hydride to the proximal
carbon atom via a five-membered cyclic transition state.
69
Scheme 2 5 . Reaction of aziridines uith some organonietallic reagents.
Table 1 Ring opening of 71 and 72 h) liydride reagents ( R ' = H )
Entr) Substrate Rcagcnt Condicions
hols have rapidly gained importance in stereoselective synthesis.
Much of their chemistry is based on regioselective ring-opening
reactions,['z61and in this section it will be demonstrated that their
aziridine counterparts. readily available in enantiomencally pure
form (see Scheme 6), are also attractive as chiral building blocks.
The basic concept is illustrated by structure 70, in which G is
a strongly activating group which can control srereochmii.strj*
1
3
5
7
71
72
71
72
71
72
71
72
73:74
Red-Al. THF. -78 C
Red-Al. T H E -78 C
LiAIH,, THF. -20 C'
LiAIH,. THF, -20 ('
DIBAL.THE -78 C - R T [ ; i ]
L>IBAL. T H E - 78 C + RT [;I]
DIBAL. C,,H,,, 0 C + RT [a]
DIBAL. C,H,. 0 C RT [a]
75:76 Y ~ l d[",o]
>99:1
>99:1
X6
x1
>O').l
80
71)
>90:1
299.1
-
50.50
30 [b]
58.42 19 [b]
20 [b]
70.30 53 [h]
[a] RT = loom temperature. [h] Incomplete reaction
G
70a
R' = H, alkyl
C-2 attack
G
70b
R' = bulky group
C-3 attack
G =activating group
by promoting clean SN2-typeattack under as mild conditions as
possible; regiochemisrry is controlled by the substituent on the
oxygen atom, which can be used to direct the incoming nucleophile to C-2 (by complexation to the attacking species) or to C-3
(by exerting steric effects).
The substrates chosen[3'. l2'I were the two translcis-pairs 71/
72 and 71'/72'; the reagents were either complex hydrides, organocuprates, or organoaluminum compounds (Scheme 26). The
results of the ring opening of 71 and 72 by the complex hydrides
Red-Al (sodium bis(2-methoxyethoxy)aluminum hydride).
The same high levels of regioselectivity were obtained in the
reactions with LiAIH, (entries 3 and 4). This also parallels the
behavior of the corresponding epoxy alcohols" 2R1 and can be
explained in the same way as the Red-Al I-esults. Interestingly,
the regioselectivity is much better for the reactions of aziridines.
which can be conducted at lower temperatures thanks to the
strongly activating N-tosyl group. Epoxy alcohols usually undergo selective C-3 attack by DIBAL.[izylbut aziridines 71 and 72
do not mimic this behavior. for reasons which are not yet clcar
(entries 5-8). However, in the case of epoxides, regioselectivity is
probably determined to some extent by complexation of Lewis
acidic reagents such as DTBAL to the epoxide oxygen atom. Such
complexation is less likely for the N-tosyl groups of 71 and 72.
Reactions with alkyl nucleophiles are synthetically more interesting, since the products of ring opening retain two contiguous stereocenters. The reagents chosen were the Gilman cuprate
L ~ M ~ , C U . [ ' ~the
' I Lipshutz "higher order" cyanocuprate
Li,Me,CuCN.[' 321 and trimethylaluminum. The results for the
rrcms-aziridines 71 and 71' are collected in Table 2. Both types of
Chiral Aziridines
REVIEWS
Table 2. K i n 2 npening o f 7 1 and 71' by methylation reagents ( R '
=
Entrv
Substrate
Rcapent.'Conditions 73:74
Yield [%]
I
4
71
71'
71
71'
>99:1
>YY:i
9?:8
>Y9.1
6
71
71'
LiMe2Cu. Et,O. -20 C
LiMe,Cu. E t 2 0 . -20 C
l.i,MeZCuCN. THF. -20 C
LilMeZCuCN. T H E - 2 0 ' C
AIMe,. foluaic. 75 C
AIMe,. toluene. 75 C
7
7
,
<I,YY
15:85
Me)
80
98
81
92
n
The transformation[L381
shown in Scheme 27 illustrates complete selectivity for ring opening a t the benzylic position of 77
and also the sometimes surprising lability" 391 of silyl ethers towards complex hydrides.
4.4. Ring Opening of Aziridine-2-carboxylates
Aziridino esters (aziridine-2-carboxylates) are potentially very
useful synthetic intermediates, since enantioselective routes to unusual amino acids (by regioselective ring-opening reactions) can
be envisaged. Leading references can be found in the recent paper
by Zwanenburg et al.,[1401who have developed a convenient
route to enantiomerically pure aziridino esters (see Scheme 6).
Some representative examples of the ring opening of both
activated and nonactivated substrates are shown in Schemes 28
and 29.
As discussed in Sections 4 and 4.1. the mechanism and regioselectivity of the acid-catalyzed ring opening of nonactivated aziridines may vary. depending on the exact conditions used. This is
1
1
4
5
6
72
72'
72
72'
72
72'
Reagen1:Conditions
LiMe,Cu EtiO, -20 C
LiMe,Cu Et,O. -20 C
Li,Me,CuCN. T H E -20 C
Li,Me,CuCN. T H F -20 C
AIMe,, toluene. 75 C
AIMc,. toluene. 75 C
75 :76
bl
-
87
13
68
< l 99
33 66
92
60
-
[a] N o reaction
the general trend of poorer regioselectivity (and lower reactivity,
entry 1 ) for the reactions of 72 and 72' as compared to the truns
isomers 71 and 71'. Presumably if complexation of the organometallic reagent to the free hydroxyl group is important for the
regiochemistry of the ring scission, the poorer performance of the
c i s isomers is mainly due to steric effects. However, ring opening
of72 with trimethylaluminum gave the same excellent C-3 selectivity a s observed for the irans isomer 71; the importance of
having a good Lewis base at the C-4 position is again underlined
by comparison of entries 5 and 6. Applications of this ringopening methodology to the enantioselectivity synthesis of some
natural products are described in Section 5.4.
HO
HCIO,. H,O
Yield [Oh]
78 22
19 21
88 1 2
(58.42)
H
79
Table -3. Ring opening of 72 and 72' by methylation reagenrs (R'= Me)
Suhstrlite
78
71
82
cupratc reagents gave very satisfactory C-2 regioselectivity (entries 1-4) irrespective of the substituent on C-4. Once again, it
seems plausible to suggest that initial complexation of the reagent
to the C-l hydroxyl group is followed by intramolecular attack
a t C-2. The corresponding epoxy alcohols behave similarly. It is
noteworthy. however, that in the reaction with LiMe,Cu aziridine
71 shows much higher regioselectivity than its epoxide counterpart,[133. 1351 0n the other hand, trimethylaluminum gave good
to excellent C-3 selectivity (entries 5 and 6). Thus, for the ring
opening of aziridine 71 complete regiocontrol can be exercised (cf.
entries I and 5 ) . Presuinably the first equivalent of the reagent
forms an aluminum alcoholate by removal of the OH proton.
This alcoholate is expected to transfer a methyl group more slowly than a trialkylaluminum species."35.
A second equivalent
of the reagent then forms a Lewis acid-base complex with the
benzyloxy group on C-4. which is followed by intramolecular
delivery of a methyl group to the proximal (C-3) carbon. Entry
6 is in line with this reasoning, since the icvt-butyldimethylsiloxy
group i n 71' should be a poorer Lewis base than the benzyloxy
group.""" As for the reaction with LiMe,Cu, the ring opening
of71 by AIMe, proceeds with much better regioselectivity than
that of thc corresponding epoxy
The results of the ring-opening reactions of the cis-aziridines
72 and 72' are shown in Table 3. Inspection of entries 1-4 shows
Entry
~~s=S irB uMe:,
Scheme 27. Regioselective ring opening of 77 accompanied by cleavage of a silyl
ether. TBS = rerl-butyldimethylsilyl.
I
"ZH
100%
Tr
80
I
49% (X = COC,H,NO,)
X
81
66% ( X = T s )
MeMgCl
N
I
CuBr(SMe,)
Me
Me H
~ c o 2 r B u
*
HNTs
Ts
55%
30%
82
X
H
X
Zn(OTf),
33.46%
I
Z
83
I
H
I
H
Scheme 28. Regioselective ring opening of nziridine-2-carboxylates. DMF
dirnethylformamide.
=
609
REVIEWS
D. Tanner
H'
HhL
H'
53%
84
HNZ
15%
gioselectivity obtained in the ring-opening reactions of both nonactivated and activated substrates. Complete C-2 regioselectivity
was observed['491for the ring opening of 90 by a cuprate reagent,
a result that may be compared to those listed in Tables 2 and 3.
In Section 2.3 the synthesis of the C,-symmetric aziridine 9
(Scheme 30) from tartaric acid was described. The C , symmetry
85
-
ArS
H
PhtjCozR'
ArSH
H,,t*,.kC02R*
N
BF3 OEt,
I
Ph
NH,
H
86
is
91
9
Scheme 30. The C,-symmetric aziridine 9 is a synthetic equivalent for the /3 cation
of L-aspartic acid: en!-9. the synthetic equivalent of the cation of waspartic acid,
can be used analogously.
87 X = H
88 X = A c
89 X = Ts
HCI I Et,O
84% (Nu=CI)
HC02H
Me,SiN,
91% (Nu = OCOH)
EtOH, DMF
56% (Nu = N3)
removes the question of regioselectivity as far as ring opening is
concerned, and the three electron-withdrawing groups in 9 make
this substrate highly susceptible to attack by n u ~ l e o p h i l e s . [ ~ ~ ]
Some results are shown In Table 4. In each case, ring opening
Me
N
LiMePCu
84%
I
Ts
90
R = SirBuMe2
+
Table 4. Ring opening of aziridine 9
' ' H
- A H
TsNH
CO,Me
Scheme 29. Regioselective ring opening of hubstituted aziridine-2-carboxylates.
In 85 and 86 R* = (-)-menthyl.
nicely demonstrated by the reactions of aziridines 79[1411
and 80
(Scheme 28)
The latter reaction provides convenient access
to stereospecifically labeled amino acids. Baldwin et al. have
described the ring opening of the activated species 81 with Wittig
(see also Section 5.3) and the copper-catalyzed reaction of 82 with Grignard reagents.['441Unfortunately, the nonactivated N-benzyl analogue of 82 was not a good substrate for
organometallic reagents, even in the presence of Lewis acids.[1251
In studies directed toward the synthesis of biologically active
natural products, Sato and K o z i k o w ~ k ishowed
~ ' ~ ~ ~that the reaction of 83 with a variety of substituted indoles was highly dependent on the nature of the Lewis acid used to promote the reaction.
The ring opening of disubstituted aziridino ester 84[1461
(Scheme 29) was completely regioselective but illustrates the
complications associated with ambident nucleophiles. Interestingly, a peptide analogue of 84 gave a single regioisomer with
sole formation of the S-acyl derivative, without the need for
Lewis acid catalysis.[1461In the nonactivated series, Marquet
et al.['47] observed complete stereo- and regioselectivity in the
ring opening of 85 and 86 by a thiol; the corresponding frans
isomers behaved similarly. (For the ring opening of nonactivated aziridinecarboxylic acids with thiols under mild conditions,
see ref. [148]). Zwanenburg et al."401 have published an extensive study of 3-alkylaziridine-2-carboxylicesters such as 87-89.
Scheme 29 shows some examples of the excellent stereo- and re-
610
Entry
Reagent
I
2
3
4
5
6
LiMe,Cu
LiBu,Cu
Li,Bu,CuCN
NaN,
MgL
MgBr,
Product
Nu
Yield
91a
Me
Bu
68
54
N,
81
12
16
Ylb
-
["A]
[dl
91 c
91 d
91 e
I
Br
[a] Decomposition
occurred with inversion under very mild conditions, which reflects
the combined activating effects of the three substituents. As
sketched in Scheme 30, the diester 9 and its enantiomer can be
considered as synthetic equivalents for the p-cation of L- and
D-aspartic acid, respectively. This approach to stereospecifically
substituted aspartic acid derivatives complements the work of
Baldwin et al.['501and Hanessian et al.,[1511who independently
developed synthetic equivalents of the corresponding anionic
synthons.
4.5. Ring Opening Promoted by Transition Metal
Complexes
has
The development of organo transition metal chemistry"
brought new dimensions to organic synthesis and greatly expanded the repertoire of techniques available for chemo-, regio-. and
stereoselective transformations. Some reactions of aziridines mediated by transition metal complexes are depicted in Schemes 31
and 32: particularly attractive are the catalytic procedures shown
in Scheme 32.
A n g w Chem In1 Ed Engl 1994, 33, 599-619
REVIEWS
Chiral Aziridines
transform aziridine 97 into fi-lactam 98 was shown to be both
regio- and stereoselective.[' 5 6 1
In the catalytic procedures shown in Scheme 32, the rhodiummediated ring expansion developed by Alper et al."571 was
shown to be both stereo- and enantiospecific, and occurred with
retention of configuration. This reaction could also be used
for kinetic resolution of aziridines, when menthol was added as
chirdl ligand. In a similar type of reaction, palladium was
used['s81 to catalyze the formation of r-methylene-/Nictams
99. Palladium was also employed by Oshima et al."591 in
an excellent synthesis of vinylpyrrolines such as 100 from
dienylaziridines. Vinylaziridines" 601 are also substrates of interest, and the palladium-catalyzed reaction['611of 101 was regioand stereoselective, yielding an azetidinone (102) of considerable synthetic potential. A related reaction conducted with
diastereo- and enantiomerically pure material is discussed in
Section 5.4.
Mek7
Me
93
C0,Me
94
SEM
I
5. Chiral Aziridines and Aziridinium Ions
in Total Synthesis
'---
3) 12
Ph
0'
I
98
50%
97
Ph
Scheme 31. Reactions of aziridines with transition metal complexes. SEM
msthylsil~lethox~methyl.
=
tri-
The ring expansion of aziridine 92 to give bicyclic compound 93
can be regarded as an "organometallic analogue" of the Stevens
rearrangement of ammonium y l i d e ~ . [ ' The
~ ~ ] process involves
the insertion of two molecules of diphenylacetylene and a
single molecule of carbon monoxide. The reaction of 94 with
[Fe(CO),] was one of the first applications of vinylaziridines." s41 The pathway proposed[' 5 5 1 for the remarkable transformation of aziridinium ion 95 into 96 provides a good demonstration ofthe mechanistic diversity exhibited by organometallic
complexes. The type of nickel-mediated ring expansion used to
H
H
N
I
co
93%
CMe,
Scheme 32. Regio- and stereoselective transformations of aziridines catalyzed by
transition inetdls.
Aii,qcii.
Ciiori Inr. Ed. EngI. 1994. 33, 599 -619
It should be clear from the foregoing sections that chirdl
aziridines are attractive building blocks for organic synthesis.
In the following discussion, representative applications of chiral
aziridines and aziridinium ions in the total synthesis of
some natural products and their analogues will be presented. In
most of these syntheses nonracemic materials were employed.
This section is subdivided according to the types of target
molecules.
5.1. Alkaloids
Oppolzer and Flaskamp['621 used the chiral aziridine 103
(Scheme 33) in an enantioselective total synthesis of pumiliotoxin-C. This elegant piece of work allowed unambiguous assignment of the absolute configuration of the natural product and
was also one of the first applications of an organometallic
reagent for the ring opening of an activated aziridine. Scheme 33
also shows a convenient enantiospecific synhesis of verruculotoxin['63] as well as a route to racemic p s e ~ d o c o n h y d r i n e , " ~ ~ ~
which made use of the thermodynamic control of the ring opening of bicyclic aziridine 104.
Tricyclic aziridines 105,[1651
106,[1661
and 107['6'1 and aziridinium ion 10S[L681
have all featured in routes to the synthetically challenging histrionicotoxin family of spirocyclic alkaloids
(Scheme 34).
The synthesis of ( + ) - ~ r o o r n i n e [ ' ~shown
~]
in Scheme 35 involved the one-pot conversion of 109 into the target molecule by
intramolecular capture of the aziridinium species 110.
Hudlicky et al." 701 have developed an ingenious and efficient
enantiodivergent route to the pyrrolizidine alkaloid trihydroxyheliotridane (Scheme 36). Starting from chlorobenzene. which
was subjected to enantioselective microbial oxidation, the synthesis diverged to give protected derivatives of both L- and Derythrose. Elaboration of both enantiomers of bicyclic vinylaziridine 111 was followed by thermal rearrangement to provide
the desired bicyclic ring systems.
61 1
REVIEWS
D. Tanner
n
103
pumiliotoxin - C
verruculotoxin
A
104
O
L
,
pseudoconhydrine
Scheme 33. Stereoreleccive synthesi? of some alkaloids from chiral aziridines. TFA
=
trifluoroacetic a c d .
CI
Pseudomonas
pubda
R = IPr
L-erythrose
o-erythrose
perhydrohistrionicotoxin
2
H
llla
Ms&
107
cph
108
R = SirBuMe,
Scheme 34. Ariridine-based routes to the alkaloid perhydrohistrionicotoxin.
i
trihydroxyheliotridanes
I .,*
Scheme 36. Synthesis
aziridines.
Me
of
trihydroxyheliotridanes
via
enantiomeric
vinyl-
5.2. Amino Sugars
109
1
110
croomine
Scheme 35. An ariridinium ion as a key intermediate in the enantioselective total
s)nrlieris of the nlkuloid croomine
612
Sugar aziridines (cf. Scheme 2) often provide convenient access
to the amino sugars found in many naturally occurring antibiotics. Two examples, in which the ring opening of both spiro and
fused bicyclic aziridines are utilized, are shown in Scheme 37.
The synthesis'"'] of the branched-chain amino sugar 113 included hydrogenolysis of aziridine 112 over Raney nickel; the
to the daunosamine deriative I15 proceeded via the
Fiirst-Plattner regioisomer (cf. Section 4.2) from the ring opening of fused aziridine 114.
A n p i . Chmz Int. Ed. Eiigl. 1994. 33, 599-619
REVIEWS
Chiral Aziridines
n
Me
Me
HO
M%oMMe
e
Z
113
HNBz
bz
BzO
OMe
N
q
o,-+
CI
114
-
NHZ
ZHN
N-Z
n
,15
Scheme 37. C'hiral ariridines in the synthesis of enantiomerically pure amino sugars.
MOM = mrthoxyinethyl. B7 = beiiroyl
5.3. Amino Acids and Derivatives
119
Baldwin et al.1'431have used the ring opening of aziridine-2carboxylates by Wittig reagents (Section 4.4) as a key step in the
synthesis of naturally occurring unsaturated amino acids (synthesis of 116. Scheme 38). In Section 2.2, a general synthesis of chiral
The 1,3-dipolar cycloaddition reactions of azomethine ylides
produced by thermolysis of aziridines have been studied very
thoroughly by Huisgen et d."'*I An interesting intramolecular
version of this reaction was used by Takano et al.L'7y1
as a key
step in the enantioselective total synthesis of acromelic acid B
U
Ph p
COzMe
I)HCHO
&
I
E10,C
NHCOAr
Scheme 39. Synthesis of an inhibitor ol' HIV-I proteasc
(119) via a chiral hisariridme. Z = henqloyycarbonyl.
HO,C
'I)
Tr
Nu
NHY
OH
-
CO,H
(CHO:
z YHN+
Nu
YHN
Y
o-mannitol
R = SrBuPh,
mugineic acid
Nu
117
Y-N
C02H (CHO)
*
JNHY
Nu
N-Y
118
*
0J
YHN$Nu
CNHY
N d
OH
c
H
o
-5 H O A ~ , ~ H ~ ~
NH,
iB0c
121
(from 120)
Scheme 40. Enantioselective routes to mugineic acid and rf:rlhro-sphingosine (121)
via chiral aziridine 120.
Scheme 3% C h i d aziridines in the synthesis of amino acids and their derivatives
N u = alkyl, halide. N.;.PhS-
bisaziridines from mannitol was presented (cf. 117 and 118,
Scheme 38). These form the basis of the elegant and convenient
route[t73]to z-amino acids and aldehydes shown in Scheme 38.
The best activating groups (Y) were tosyl and benzyloxycarbonyl,
and a very thorough study of twofold ring-opening reactions with
a wide range of nucleophiles was performed. Oxidative cleavage
of the central 1,2-diol moiety finally provided two molecules of
chiral product per molecule of substrate. The same mannitol
derivatives could be used for the synthesis["4' of C,-symmetric
inhibitors of HIV-1 protease (119, Scheme 39, cf. [175]).
The Paris group" 761 has also reported an enantioselective
approach toward mugineic acid. The chiral aziridine 120
(Scheme 40) was synthesized from 2-O-benzyl-~-threitoIand
could be converted in a few steps (including regioselective ring
opening by phenylthiolate) to an advanced key intermediate.
Aziridine 120 is also a possible precuror to optically active
rr,.t/zro-sphingosine (121) .['"I
Angiw. C'ht'm. In,. Ed. EngI. 1994. 33. 599- 619
from (S)-0-benzylglycidol (Scheme 41). Thermolysis of a 50: 50
mixture of aziridine epimers 122 gave a single stereoisomer of
pyrrolidine 123. which was then elaborated to the target molecule by a sequence involving epimerization at C-2.
Bn 122
200 oc
OBn
+
...."\
HN /
HO,C
CO,H
C0,H
H
123
acrornelic acid B
Scheme 41. Ariridine 122 as a key intermediate in the enantioselective total synthcsis of acromelic acid B.
61 3
REVIEWS
D. Tanner
5.4. P-Lactam Antibiotics
In Sections 2.4 and 4.3 the synthesis and ring-opening reactions of enantiomerically pure 2,3-aziridino alcohols were described. It will now be demonstrated how this methodology can
be applied to the enaiitioselecttve synthesis of some members of
the important class of carbapeiiem antibiotics. The target molecules and the types of key intermediates for their total synthesis
are shown in Scheme 42
regioselectivity of the ring opening, now dictated by the benzyl
moiety (Section 4.3), is complete in both cases. The route via
127 is particularly efficient in terms of overall yield.[t811
Me
H
O
W
O
R
AIMe,
65%
N
Ho
Ts
R'
t?
Me
S(CH),NHR3
thienamycin R' =OH, R2,R3 = H
PS-5 R', R' = H. R3 = AC
l~-Me-thlenamycin
R1 =OH, R Z = Me, H3 = H
-
__t
J-
HNTs
1P-methylthienamycin
NIH
126
C0,H
Me
Me
CO,H
key intermediates
for thienamycin
for PS-5
for 18-Me-thienarnycin
Scheme 42 K e j intermedidtes for the enantio~electnesynthesis of some cdrbdpenem dntihlotics
Me
4126
The synthesis of these three key intermediates relies on the
regio- and stereoselective ring opening of suitable aziridino alcohols by Red-Al, LiEt,Cu, and AlMe, , respectively. rrans-Aziridines were used in the routes to thienamycin, via 124,["] and
PS-5: from 125f1801(Scheme 43). The C-2 regioselectivity was
F!
is
127
Scheme 44 Use of L I \ ,imidino cilcoholz in the aknthesiu of 1P-methylthiendmycin
R = PhCH,
All four of the required aziridino alcohols can be obtained in
> 90 YOee from the corresponding epoxides. The tosyl group not
only activates the ring toward nucleophilic attack but also is
Ts
IS
125
R = SiBuMe,
important for efficient closure of the azetidinone ring under
mild
Non-natural analogues of these antibiotics
are equally easily available by this route simply by suitable permutations of the cis or frans geometry of the allylic alcohol used
in the Sharpless AE reaction, the ( + ) or ( - ) enantiomer of the
tartrate ester serving as a ligand in the AE reaction. and the
nature of the nucleophile used in the ring opening of the activated aziridine.
A complementary
for the synthesis of PS-5 is
shown in Scheme 45. Key steps in this stereoselective route are
R = SirBuPhp
,25
Scheme 43. Enantiomerically pure rum aziridino alcohols provide a route to the
carhapenem antibiotics thienamycin and PS-5.
excellent in both cases, presumably owing t o the directing effects
of the free hydroxyl group (cf. Section 4.3).
cis-Aziridines were used in two approaches['"] to lp-methylthienamycin (via key intermediate 126); the second route involved chiral aziridines at two different stages (Scheme 44). The
614
l)TPAP+
2) Wittig rxn.
77%
N
Ts
128
"
R = SirBuPh,
Scheme 45. A stereoselective palladium-catalyxed transformation of a vinylariridine to an enantiomerically pt11-e[~-laCtdlll.TPAP = retra-r~-propylammoniu~
perruthenate, R = SiiBuPh,.
Avgrbi CIIPIII
frrr. Ed Erigl 1994, 33. 599 619
REVIEWS
Chiral Aziridines
the palladium-catalyzed ring opening of vinylaziridine 128, followed by insertion of CO and ring closure to the a-lactam (cf.
Section 4.5).
. ..
'\7
R'
5.5. Some Natural Products Containing Aziridine Units
'?
The C,-symmetric aziridine 129 can be synthesized[1841in a few
steps from (+)-tartaric acid (cf. Scheme 3). Not surprisingly, the
other much more intricate structures have prompted much synthetic activity; the most effort['851 has been devoted to the
134
+
133 a R =OCH,
b R = OCHZPh
c R = C,H7
dR=Ph
c
Ph
135
Scheme 46. Use of C,-symmetric ariridiiies as chiral auxiliaries for diastereoselective alkylation with alkali metal bis(trimethylsily1)amides and beniylbromide.
MeO%
N-H
HZ
Me
H
129
Entry
Substrate
Me
1.34: 135
133a
133 b
133 b
133b
133c
133d
L1
>YY:l
LI
Na
>90:1
75:25
67:33
80:20
15:25
0
130 mitornycin A
Hd
131 FA-900482
Table 5 . Diastereoselective alkylation of 133 with MN(SiMe,), and PhCh,Br.
132 azinomycin A
mitomycins. (The first total synthesis of racemic mitomycin A
was accomplished by Kishi et al.L1s61
as early as 1977.) Racemic
FR-900482 was synthesized very recently by Fukuyama
et al.,['871and an enantiospecific approach from L-methionine
(via an aziridine closely related to compound 31 in Scheme 19)
has also been reported.[ls8I Coleman and Carpenter" 891 have
disclosed a stereoselective route from D-glucosamine to the
aziridine substructure of the azinomycins.
6. Aziridines as Chiral Auxiliaries for Asymmetric
Synthesis
As shown in Section 2.3, tartaric acid provides convenient access to C,-symmetric chiral aziridines. Scheme 46 shows how
these materials can be used as chiral auxiliaries[251for diastereoselective alkylation. The enolates of amides 133a-d were
formed at low temperature and allowed to react with various
electrophiles. Results from the alkylations with benzyl bromide
(Table 5 ) illustrate some of the interesting features of the reaction. The lithium enolates of aziridines 133a and 133b, which
have ether side chains, reacted with complete diastereoselectivity to give the alkylated products with the absolute configuration
shown for 134 (Table 5, entries 1 and 2). For 133b the effect of
varying the counterion of the enolate was studied; lithium was
found to be far superior to sodium o r potassium (entries 2-4).
The importance of the nature of the cation and insensitivity of
the steric bulk of the alkoxy group suggests that a chelate is
formed between the metal ion and an oxygen atom in the enolate
and one In the side chain. This hypothesis was tested by studying
K
LI
LI
the reaction of aziridines 133c and 133d (available in enantiomerically pure form by the Sharpless asymmetric dihydroxylation procedure) ,[1901 which have two relatively bulky side
chains with no donor atoms for chelate formation (entries 5 and
to explain the results is provided by
6). A simple
structure 136. Under the reaction
/R
conditions used, the ( Z ) enolate is
0
1
formed,~'"l and the enolate species
Ro/
LI
is presumed[1921to have a pyrami.+o/
dalized nitrogen atom. Chelation of
Me
the metal ion (expected to be most
136
favorable for lithium) then directs
the incoming electrophile to the opposite face of the enolate,
which results in the absolute configuration observed in the products. Since the substrate has C, symmetry, it makes no difference on which face of the aziridine ring the chelate is formed.
The importance of the symmetry element['931is emphasized by
the results of the reaction shown in Scheme 47.
6
0
\ I
-0
6
"
6\
1\ I iHMnS
I
0
6
"
N
Ph
Scheme 47. Poor diastereoselectivity (75: 2 5 ) in thc alkylation of a non-C',-symmetric substrate. LiHMDS = lithium heximethyl dlsilazide.
Much effort has been expended on the development of asymmetric versions of the aldol
Since many of the most
successful approaches are based on the use of chiral auxiliaries.
it was of interest to test the performance of the C,-symmetric
aziridines. Four diastereomeric products are possible for the
aldol reactions (Scheme 48).
61 5
REVIEWS
D. Tanner
HO
summarized by Seebach and Hiiner,[l"sl the generation and
handling of "carbanionic" three-membered heterocycles can be
problematic. Some successful solutions to this problem are discussed below (Schemes 49 and 5 0 ) .
AZ"
137
Me
138
139
140
Me
133 ad
+
-
Scheme 48. Four possible diastereomers may result from an aldol reaction in Nhich
ii chiral ariridiiie auxiliary ( A L * )is used.
n
0
One important stereochemical factor is the enolate geometry.
( Z )Enolates of the type used here tend to give syn-aldol products under conditions of kinetic control. The
AZ'
Zimmerman-Traxler model of the transition
state (141) has gained widespread use for exR
+
flo
';
plaining the stereochemical outcome.[1y11
A
selection of results['5. '1
is shown in
Me
141
Table 6.
0
II
0
Ph
: : II
N
l t b l e 6. Dinatereoselective aldol reaction5 of 133 and R'CHO.
+cl
P(OE0,
1) BuLi
P(OEI),
Ph
2) CCI,
N
85%
Entry
Suhstra te
R'
137: 138: 139.140
Ph
Ph
144
3
133a
l33b
133c
4
5
6
I
133 b
133c
l33d
1
7
133d
Ph
Ph
Ph
Ph
Et
Et
Et
X7:13. < 1 : < 1
y9:1:<1:<1
>9Y:<l:<l:<t
91:9:<1,<1
40: 40: 10 : 10
87: 13: i l : i l
XS:IS:<l: < I
Bis(benzy1oxymethyl)aziridine 133 b gave excellent results only
with relatively bulky aldehydes (cf. entries 2 and 5 ) . while the
bis(methoxymethy1) species 133 a was even less selective (entry 1 ) .
This behavior does not parallel that observed for the alkylation
reactions (cf. Table 5 ) . Another significant difference is the much
improved performance of auxiliaries having side chains not containing oxygen atoms (entries 3. 4, 6. 7). For the ZimmermanTraxler mechanism to be operative, the metal ion must be able to
coordinate simultaneously to both the enolate and the aldehyde
oxygen atoms. This is not possible if the metal ion is already
coordinated to the side chain of the auxiliary. In the special case
of the reaction between 133 b and benzaldehyde (entry 2) the
diastereoselectivity appears to be entirely due to steric effects on
the approach of the aldehyde to the enolate. For the reactions
involving auxiliaries without oxygen atoms in their side chains,
the Zimmerman-Trdxler transition structure (141) is assumed.
The C,-symmetric aziridines discussed here thus fulfill the usual requirements for a good chiral auxiliary : both enantiomeric
forms are readily available; they give good to excellent rle in
subsequent reactions; and they can be removed easily["41 in a
nondestructive manner.
Scheme 49. Stcreoselective i-eactions with metalated arirtdines ;is chiral intermcdiates. Top: R = CH,. C,H,CH,. CHI=CHCH,: middle: E = Mel. C,H,CH,Br.
C,H,CHO, /]-nitrostyrene,
The 2-phenylsulfonylaziridine142 could be nietalated and then
alkylated with reactive alkyl halides in excellent yield (Scheme
49)
Racemic compounds were used and, unfortunately. no
stereochemical information was provided. Seebach et al. have
published the results of a careful study of the lithiation and subsequent reactions of both race mi^['^^] and enantiomerically
pure[1971(S)-phenyl aziridinecarbothiates 143; electrophilic substitution was shown to occur with retention of configuration.
Lithiated (racemic) aziridinylphosphonate 144 could not be alkylated or trapped by aldehydes but did react with carbon tetrachloride; in this case. inversion of configuration was suggested." 9Rl
Ph
Me
i
=
H
- -
N
I
Ph
145
,s
To,
1) EiMgBr
Ph Me
H+
N
2) MeCHO
OH
Me
I
85%
Ph
0
Q
80%
146
RO
147
RO
7. Aziridines as Chiral Reagents
The reaction of chiral metdlated aziridines with electrophiles
has obvious potential for stereoselective synthesis. However, as
616
Scheme 50. Further examples of the use of configurationally ?table "carbnnionic"
ariridine species. Q IS g \ e n in Scheme 11
A n f ~ i ~ Chrm.
'.
Inr.
Ed. En,ql. 1994, 33. S99-hlO
REVIEWS
Chiral Aziridines
The suliinylaziridine 145 (which can be obtained in enantiomerically pure form, see Section 2.6) was transformed to the corresponding Grignard reagent. which could be trapped by acetaldehyde but not with alkyl halides (Scheme 50) .[761 An aziridinyl
carbanion was implicated in the efficient sequence[1991leading
from 146 to 147. Vedejs and Moss[2oo1have described the preparation of configurationally stable (racemic) aziridinyllithium
reagents by t i n -lithium exchange[2011on aziridines such as 148;
the lithiated species could be trapped efficiently by a range of
electrophiles. and an interesting anionic Stevens rearrangement
was also observed.
Two interehting examples ofchiral reagents formed from ringopening reactions ofaziridines are shown in Scheme 51. A chiral
Mitsunobu rxn.
(>80% overall)
N
153
oso,
Ph
153 (R = Ph)
' O x p h
Ph
OH
90% yield
95% ee
Scheme 52 Synthesis of C',-syminetric bmziridine ligands and h e i r use
tiosclcctive synthesis.
111
enan-
9. Summary and Outlook
H
Boc
149
E:Z=2:1
.. .
151
150
Schemc 51 Forination a i d rraction o f chirdi reagents from the ring opening of
aziridnic\.
Wittig reagent was prepared from the enantiomerically pure
azil-idine 149 and used for the synthesis of optically active allylic
amines,[20'1 Yus et al. obtained a single diastereoiner of 151
of
from the naphthalene-lithium catalyzed ring
(racemic) aziridine 150 followed by quenching with D,O.
Chiral aziridines are readily available in enantiomerically pure
form by a variety of procedures, and the reactivity of these
three-membered heterocycles can be modified by suitable choice
of the substituent on the nitrogen atom. Regio- and stereoselective ring-opening reactions with many types of nucleophiles
provide access to a great number of useful synthetic intermediates. In addition to being attractive substrates o r "building
blocks" for the organic chemist, aziridines can also function as
chiral auxiliaries, chiral reagents. and chiral ligands for asymmetric synthesis.
The utility of chiral aziridines in organic synthesis will be
further enhanced by the development of improved general procedures for the catalytic enantioselective aziridination of olefins.
But it seems appropriate even now to close this review by paraphrasing the title of an article by Sharpless et
Chiral
aziriciines-- like epoxidcs mil!*even mow wrsatilc~.
8. Aziridines as Chiral Ligands.
Toward Enantioselective Catalysis
Many of the most exciting recent developments in stereoselective orpanic synthesis are based on transition metal catalyzed
processes. and the rational design of chiral ligands for enantioselective catalysis presents a foimidable challenge.['*'] Aziridines can be employed not only in the preparation of such chiral
species 1 2 0 s . 2061 but should also be useful ligands in their own
right. Trisaziridine 152 is an (achiral) ligand
H
N
'
NNH
and just one of a series of fascinating compounds prepared and studied by Prinzbach
pJ
et
a1.[2071
A general approachr2081to C',-symmetric
bisaziridine ligands is shown in Scheme 52.
Two equivalents of a rraizs-epoxide are ring-opened by one
equivalent of a diamine, and the resultant species is subjected to
a double Mitsunobu ring closure. In a stoichiometric reaction
ligand 153 mediates the enantioselective sjn-dihydroxylation of
ri.cin.s-stilbene i n excellent chemical yield and with 95% re. Current work focuses on the development of catalytic procedures
for this and other reactions, for example enantioselective cyclopropanation and aziridination.
152
[ I ] H. Heimgartncr. Anxew. C/wni. 1991, 103. 271: Anycii. C / i ~ n /i n. r . Ed. Enpi.
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,
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'
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[I41 H. Paulscn. H. Patt. Liebig, Ann Chmi 1981. 1633.
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61 9
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