A regio- and stereoselective approach to quaternary centers from chiral trisubstituted aziridines

Article abstract of DOI:10.1021/ja0758077

A thorough investigation of a regio- and stereospecific aziridine ring opening reaction presents new synthetic technology for the construction of a variety of quaternary β-substituted-α-amino functional groups. Mild, metal-free reaction conditions allow f

Full text of DOI:10.1021/ja0758077

Published on Web 10/31/2007
A Regio- and Stereoselective Approach to Quaternary Centers
from Chiral Trisubstituted Aziridines
Erin M. Forbeck, Cory D. Evans,† John A. Gilleran, Pixu Li,‡ and
Madeleine M. Joullie´*
Contribution from the Department of Chemistry, UniVersity of PennsylVania,
231 South 34th Street, Philadelphia, PennsylVania 19104
Received August 2, 2007; E-mail: mjoullie@sas.upenn.edu
Abstract: A thorough investigation of a regio- and stereospecific aziridine ring opening reaction presents
new synthetic technology for the construction of a variety of quaternary â-substituted-R-amino functional
groups. Mild, metal-free reaction conditions allow for application in highly functionalized systems. This
reaction has been applied to the challenging stereoselective formation of tertiary alkyl-aryl ethers. The
strategy for the formation of these hindered ethers has been investigated using a variety of functionalized
aziridines and phenols to determine the scope of the reaction. Other nucleophiles, such as thiolate, azide,
and chloride, have also been examined to encompass the synthesis of a broader range of functionalities.
This aziridine ring opening reaction manifold has demonstrated utility in assembling: â-substituted-R-amino
carboxamides, â-substituted-R-amino esters, â-substituted-R-amino silyl ethers, â-thio-R-amino carboxa-
mides, â-azido-R-amino carboxamides, and â-halo-R-amino carboxamides. Studies to probe the effect of
the aziridine substitution patterns show that alkyl aziridines display similar reactivity to alkynyl aziridines,
giving insight into mechanistic possibilities.
substituted carbon of the aziridine.5,6,13 Ring opening of aziri-
dines by oxygen nucleophiles is also limited and usually occurs
Introduction
Aziridines are important intermediates in organic synthesis
due to a highly strained ring system1 that allows for a range of
reactivity, and the utility of aziridine ring opening reactions has
been extensively studied.2-8 Nucleophilic ring opening reactions
are particularly important in exploiting aziridines as synthetically
useful intermediates.9 However, di- and trisubstituted aziridines
often show diminished regioselectivity and reactivity as elec-
trophiles. This shortcoming limits the versatility of aziridines
as synthetic intermediates. Very few non-Lewis acid-catalyzed
intermolecular nucleophilic reactions are known to show a
regioselective preference for attack at the more substituted
carbon of the aziridine ring.10-12 Lewis acid-catalyzed reactions
benefit from quaternization of the nitrogen atom, but under basic
conditions there is usually regioselective preference for the less
under acid catalysis.9
We recently reported the discovery of an ethynyl aziridine
ring opening reaction.14 Copper-catalyzed substitution reactions
of propargyl halides and carbonates provided the impetus for
this reaction (Scheme 1).15,16 These reported reactions employed
achiral substrates and were by virtue not stereoselective;
however, we were able to achieve stereoselectivity when using
chiral nonracemic aziridines under similar conditions. The
stereoselective reaction under mild conditions has allowed for
incorporation into a total synthesis of the microtubule inhibitor
ustiloxin D, where this transformation was used to form the
challenging chiral tertiary alkyl-aryl ether moiety.17 This ring
opening reaction led to a more convergent and robust synthesis
and has recently allowed for the preparation of several analogues
to probe the structure activity relationship of the ustiloxins.18
† Current Address: Food and Drug Administration-CVM, MPN2 RME
324 HFV-142, 7500 Standish Place, Rockville, MD 20855.
‡ Current Address: Wyeth Research, 401 N. Middletown Rd., Pearl
River, NY, 10965.
(1) Cox, J. D. Thermochemistry of organic and organometallic compounds;
New York University Press: London, 1970; p 643.
(2) Lee, W. K.; Ha, H. J. Aldrichimica Acta 2003, 36, 57.
(3) Tanner, D. Pure Appl. Chem. 1993, 65, 1319.
(4) Tanner, D. Angew. Chem. 1994, 106, 625.
Further applications of this reaction have allowed for the
synthesis of a variety of â-substituted-R-amino functionalities.
Some quaternary â-substituted amino acids are components of
enzyme inhibitors,19 and their incorporation into peptides is used
(5) McCoull, W.; Davis, F. A. Synthesis 2000, 1347.
(6) Sweeney, J. B. Chem. Soc. ReV. 2002, 31, 247.
(7) Dahanukar, V. H.; Zavialov, L. A. Curr. Opin. Drug DiscoVery DeV. 2002,
5, 918.
(13) Chemla, F.; Ferreira, F. Curr. Org. Chem. 2002, 6, 539.
(14) Li, P.; Forbeck, E. M.; Evans, C. D.; Joullie´, M. M. Org. Lett. 2006, 8,
5105.
(8) Padwa, A.; Murphree, S. S. ARKIVOC 2006, 6.
(9) Hu, X. E. Tetrahedron 2004, 60, 2701.
(15) Godfrey, J. D.; Mueller, R. H.; Sedergran, T. C.; Soundararajan, N.;
Colandrea, V. J. Tetrahedron Lett. 1994, 35, 6405.
(10) Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J. Tetrahedron Lett.
1997, 38, 5253.
(16) Bell, D.; Davies, M. R.; Geen, G. R.; Mann, I. S. Synthesis 1995, 707.
(17) Li, P.; Evans, C. D.; Joullie´, M. M. Org. Lett. 2005, 7, 5325.
(18) Li, P.; Evans, C. D.; Forbeck, E. M.; Park, H.; Bai, R. L.; Hamel, E.; Joullie´,
M. M. Bioorg. Med. Chem. Lett. 2006, 16, 4804.
(19) Formaggio, F.; Baldini, C.; Moretto, V.; Crisma, M.; Kaptein, B.;
Broxterman, Q. B.; Toniolo, C. Chem.-Eur. J. 2005, 11, 2395.
(11) Lin, P.-y.; Bellos, K.; Stamm, H.; Onistschenko, A. Tetrahedron 1992,
48, 2359.
(12) Sureshkumar, D.; Gunasundari, T.; Ganesh, V.; Chandrasekaran, S. J. Org.
Chem. 2007, 72, 2106.
9
10.1021/ja0758077 CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 14463-14469
14463

A R T I C L E S
Forbeck et al.
Scheme 1. Literature Precedent for Propargyl Substitution16
Chart 1. Previous resultsa of aziridine ring opening reactions by
phenols.14
to modulate secondary and tertiary structural conformations.20
Synthesis of these amino acids stereoselectively would allow
for an opportunity to examine their effects in biological systems.
Formation of quaternary â-substituted compounds is not trivial,
despite widespread interest in their functions. Stereoselective
addition to â,â′-disubstituted amino acids or amines is chal-
lenging because the R-position is prone to epimerization and
construction of a chiral quaternary center by an SN2 reaction is
also problematic since elimination of an amino acid or ester to
an enone is often an undesired side reaction. Use of a
nucleophilic ring opening reaction in the formation of hindered
quaternary centers is not a traditional transformation. To this
end, we now wish to present a stereospecific nucleophilic ring
opening that displays complete regioselectivity for the more
substituted carbon of a trisubstituted aziridine.
We previously reported a method for tertiary alkyl-aryl ether
synthesis from nosyl and tosyl aziridines with CuOAc, DBU,
and a p-substituted phenol nucleophile.14 Phenols were chosen
because there are limited examples of aziridine ring openings
by oxygen nucleophiles.21,22 Additionally, variation of the
electronic properties of the phenolic functional groups would
determine whether the substituents of the aromatic ring affected
reactivity. Chart 1 shows results from our previous studies in
which aziridines 1 and 2 underwent ring opening with inversion
of stereochemistry. The faster rate of reaction of the nosyl
aziridine may be due to the electronic properties as nosyl
aziridines are known to be better electrophiles than tosyl
aziridines.10 The reaction was not significantly dependent
upon the substitution of the phenol as the yields with most
phenols are comparable. Surprisingly, the reaction of the tosyl
aziridine 1 with p-cyanophenol and p-hydroxybenzaldehyde
(Chart 1, 7 and 8) gave low yields. Initially, we did not have a
rationale for these low yields, but more recent observations
suggest that this anomaly results from further undesirable
reactivity of the product rather than diminished reactivity of
p-cyanophenol or p-hydroxybenzaldehyde with the tosyl aziri-
dine 1.
Results and Discussion
Synthesis of Aziridines. To thoroughly study the scope of
the aziridine ring opening reaction, several aziridines were
synthesized by slight modifications of our previously reported
method (Scheme 2).17 Grignard addition of ethynyl magnesium
bromide to methyl ketone 15 resulted in diastereomeric tertiary
alcohols 16 and 17 in 80% yield and a ratio of 1:11,
respectively.23,24 Conveniently, these diastereomers were sepa-
rable and were used to synthesize all of the desired aziridines.
The N,O-acetal of 17 was removed with HCl, and the amine
was subsequently protected with p-toluene sulfonyl (tosyl)
chloride. A TEMPO catalyzed oxidation of the primary hydroxyl
group directly gave carboxylic acid 18 in a single step. A
a Conditions: p-R1-phenol (2 equiv), DBU (2.2 equiv), CuOAc (2 mol
%), Toluene.
carbodiimide coupling of 18 with Gly‚OMe‚HCl followed by
Mitsunobu ring closure gave aziridine 1. The N-nosyl diol 19
was synthesized from 17 by removal of the N,O-acetal followed
by protection of the amine with 2-nitrobenzenesulfonyl (nosyl)
chloride in quantitative yield. Again, a TEMPO catalyzed
oxidation of the primary hydroxyl group gave acid 20. Coupling
of the acid with Gly-OtBu‚HCl followed by Mitsunobu ring
closure gave aziridine 2. The synthesis of aziridine 22 began
with esterification of acid 20 with benzyl bromide in 73% yield
followed by Mitsunobu ring closure with DIAD and PPh3 in
(20) Augeri, D. J., et al. J. Med. Chem. 2005, 48, 5025.
(21) Papa, C.; Tomasini, C. Eur. J. Org. Chem. 2000, 1569.
(22) Guthikonda, K.; DuBois, J. J. Am. Chem. Soc. 2002, 124, 13672.
(23) Ageno, G.; Banfi, L.; Cascio, G.; Guanti, G.; Manghisi, E.; Riva, R.; Rocca,
V. Tetrahedron 1995, 51, 8121.
(24) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis 1998, 1707.
9
14464 J. AM. CHEM. SOC. VOL. 129, NO. 46, 2007

Quaternary Centers from Trisubstituted Aziridines
A R T I C L E S
Scheme 2. Synthesis of Aziridines from Methyl Ketone 15
Scheme 3. Ring Opening Reaction of Silyloxy Aziridine 23
40% yield. The (R,S)-silyloxy aziridine 23 was synthesized from
diol 19 by protection of the primary hydroxyl as its tert-butyl
dimethylsilyl ether followed by Mitsunobu ring closure in
excellent yield. (S,S)-Silyloxy aziridine 25 was synthesized from
intermediate 16 by removal of the N,O-acetal and subsequent
protection of the amine as its nosyl sulfonamide to give 24 in
74% yield. The primary hydroxyl was protected as its tert-butyl
dimethylsilyl ether, and Mitsunobu ring closure was employed
to give aziridine 25.
Side Products and Their Origin. The silyloxy aziridine was
designed to determine whether the electron-withdrawing C3
carboxamide substituent of the aziridine was the controlling
factor in the regioselectivity or whether other substituents would
display similar regioselectivity in the aziridine ring opening.
As in the case of the carboxamide aziridines, ring opening of
silyloxy aziridine 23 proceeded regio- and stereoselectively.
However, the reaction took several days to complete rather than
24 h. This result showed that the reaction was not limited to
aziridine carboxamides, and that perhaps there was some
underlying factor for selectivity. Interestingly, under the reaction
conditions, byproducts formed along with the desired product
26 (Scheme 3). The structure of the first undesired compound
was determined by X-ray crystallography to be pyrrole 27,
which was inseparable from the desired ether. The second
byproduct was enyne 28.
of these reactions involving aziridine 23 gave any amount of
pyrrole 27, it appeared that the pyrrole might be formed from
the desired alkyl-aryl ether 26. To test this hypothesis, alkyl-
aryl ether 26 was treated with CuOAc and DBU in toluene
(Scheme 4). This reaction gave a trace amount of enyne
byproduct and a 19% yield of pyrrole 27 along with unreacted
ether 26. This observation suggested that 27 may be the
thermodynamically favored product and that longer exposure
to the reaction conditions may result in lower yields of the
desired product 26. We concluded from this study that the
pyrrole byproduct was formed from the alkyl-aryl ether whereas
the enyne byproduct was formed predominantly from the
aziridine.
Scheme 4. Study of Enyne and Pyrrole Formation
Because the pyrrole byproduct was formed from the ether
over time, attempts to increase the rate of the reaction were
expected to decrease pyrrole concentration. A stronger base
(KHMDS), higher temperatures (50 or 80 °C), a polar solvent
(MeCN), and higher CuOAc catalyst loading (10 mol %) were
employed to increase the rate of the reaction; however, all
conditions failed to improve the results. Notably, higher catalyst
loading and more polar solvents resulted in a higher yield of
byproducts. This observation led us to lower the catalyst loading.
To our surprise, optimal yields of the desired product 26 were
obtained when CuOAc was not used in the reaction. These new
conditions resulted in the formation of the desired ether product
A set of experiments was devised to determine the origin of
the byproducts, and these reactions were allowed to stir until
some side product was observed (1-5 days). When aziridine
23 was treated with CuOAc and DBU in toluene, enyne 28 was
observed. When aziridine 23 was treated solely with DBU in
toluene, enyne byproduct 28 was also observed. Since neither
9
J. AM. CHEM. SOC. VOL. 129, NO. 46, 2007 14465

A R T I C L E S
Forbeck et al.
Table 1. Study of the Role of CuOAc
conditions
12
29
1: CuOAc (1 mol %) DBU (2 eq)
2: DBU (2 eq)
77%
77%
0%
0%
3: CuOAc (1 eq)
<3%
39%
Scheme 5. Proposed Mechanism of Pyrrole Formation
along with enyne 28. The pyrrole byproduct 27 was absent when
CuOAc was not used in the reaction. A test reaction was
performed to determine the optimal catalyst loading of
CuOAc since the reactions of the silyloxy aziridine 23 gave
cleaner results without CuOAc. Reaction of p-bromophenol and
DBU with aziridine 2, the most reactive aziridine, gave
identical yields of ether 12 with and without CuOAc (Table 1,
entries 1 and 2).25 These results clearly show that copper is not
a required catalyst since ring opening in both the presence and
absence of CuOAc gave identical yields and selectivities.
Although CuOAc was not necessary, it was important to
determine whether CuOAc itself could promote reactivity.
Reaction with stoichiometric CuOAc did provide a trace amount
of ether 12; however, the predominant product was enyne 29
(Table 1, entry 3).
This observation was important as we believed the yield of
the reaction of aziridine 1 with p-hydroxybenzaldehyde (Chart
1, 8) could be increased by eliminating the copper catalyst.
However, reaction of aziridine 1 with and without CuOAc
afforded some undesired pyrrole byproduct. Increased pyrrole
formation was observed when electron-deficient phenols were
used in the reaction as they likely functioned as stable leaving
groups after the initial formation of the alkyl-aryl ether products.
The difference in pyrrole formation between the nosyl and tosyl
aziridines may be attributed to the greater nucleophilicity of
the tosyl sulfonamide as compared to the nosyl sulfonamide,
allowing for more facile attack on the terminal alkyne in this
system. A suggested mechanism based on these results is shown
in Scheme 5. After ring opening of the aziridine, the N-
sulfonamide anion may attack the terminal carbon of the
acetylene to form a 5-membered ring in a 5-endo-dig cyclization.
Anti-elimination of the stable phenoxide would allow for
aromatization to give the pyrrole. Knight and co-workers found
that pyrrole formation from anti-γ-ynyl-â-hydroxy-R-amino
esters under various conditions proceeded in good yield.26,27
Although we favor the mechanism involving cyclization fol-
lowed by elimination, it is also possible that elimination of the
phenol precedes cyclization. This elimination would give a (Z)-
enyne that might be poised for cyclization.28 While CuOAc
seemed to contribute to pyrrole formation in the case of silyloxy
aziridine 23, removal of CuOAc from the reaction of aziridine
1 did not diminish pyrrole formation. As such, it was necessary
to find conditions that would optimize the yield of the desired
ether and eradicate pyrrole formation.
Optimization of Conditions and Scope of Aziridine Sub-
strate. In recent years, particular emphasis has been placed upon
the use of strong neutral organic bases in organic synthesis.
Bicyclic guanidine bases such as commercially available 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (also known as 2,3,4,6,7,8-hexahy-
dro-1H-pyrimido[1,2-a]pyrimidine, TBD), are known as super-
bases due to their high pKa values (TBD pKa 26) and facile
solubility in organic solvents.29,30 Neutral organic bases, com-
pared to ionic bases, have a distinct advantage in that they allow
for milder reaction conditions. Although strong guanidine bases
have been known for some time and are useful for synthetic
purposes, little work on their use in organic synthesis was
reported until recently. Some examples have shown that TBD
exhibits bifunctional hydrogen-bonding capabilities that cannot
be realized with traditional ionic bases.31,32
It was found that in the absence of CuOAc stronger bases
gave better yields in the aziridine ring opening; due to this
property and to the success of TBD as a nonionic base in several
organic transformations, we decided to replace DBU with TBD.
This modification substantially increased the yields and mini-
mized pyrrole formation. Chart 2 shows a comparison of the
yields with the initial reaction conditions (CuOAc, DBU,
toluene) to the newly optimized reaction conditions (TBD,
toluene) for aziridine 23. The new conditions also greatly
facilitated purification of the desired ethers since the inseparable
pyrrole product was not formed. The most dramatic increase in
yield was in the reaction of p-bromophenol and aziridine 23
(25) In the reaction without CuOAc, metallic contamination was avoided by
using a new stirbar and glassware. No needles were used to transfer solvent
or reagents to prevent metal leaching.
(29) Schwesinger, R. Chimia 1985, 39, 269.
(30) Schwesinger, R. Nachr. Chem. Tech. Lab. 1990, 38, 1214.
(31) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157.
(32) Pratt, R. C.; Lohmeijer, B. G. G.; Long, D. A.; Waymouth, R. M.; Hedrick,
J. L. J. Am. Chem. Soc. 2006, 128, 4556.
(26) Knight, D. W.; Sharland, C. M. Synlett 2003, 2258.
(27) Knight, D. W.; Sharland, C. M. Synlett 2004, 119.
(28) We thank a reviewer for pointing out other possible mechanisms.
9
14466 J. AM. CHEM. SOC. VOL. 129, NO. 46, 2007

Quaternary Centers from Trisubstituted Aziridines
A R T I C L E S
Chart 3. Ring opening reactions of benzyl aziridine 22 with
Chart 2. Comparison of reaction conditions with aziridine 23 and
results of ring opening of aziridine 25.
p-substituted phenols.
philes were studied. For completeness, aziridine 2 was treated
with o- and m-bromophenol and gave comparable yields to those
with p-bromophenol. Both o- and p-bromophenol gave the
desired ether in 78% yield while m-bromophenol gave the
desired product in 72% yield. Because these differences are
within experimental error, these reactions further confirm that
the electronics of the phenol do not significantly affect the
reaction outcome. Ring opening of aziridine 2 with thiophenol
gave an acceptable yield of thioether 42 at a rapid rate, albeit
with a higher percentage of pyrrole byproduct (Scheme 6).
Increased pyrrole formation was likely due to the leaving group
ability of thiophenoxide.
Wu and co-workers have reported regioselective ring opening
of mono-, di-, and trisubstituted alkyl aziridines with tri-
methylsilyl reagents at the less substituted aziridine carbon.33
However, reaction of aziridine 2 with TMSN3 gave excellent
regio- and stereoselectivity for the more substituted propargylic
carbon to give â-azido-R-amino carboxamide 43 (Scheme 6).
This reaction is synthetically useful since the azide can be further
modified to incorporate a variety of functional groups. More
interestingly, reaction of aziridine 2 with TMSCl gave â-chloro-
R-amino carboxamide 44 stereo- and regiospecifically in good
yield (Scheme 6). Since tertiary chlorides are exceptionally
difficult to synthesize in a stereodefined manner and chloride
is not a particularly strong nucleophile this further highlights
the unique reactivity of these aziridines. Additionally, this is a
remarkable result considering that the chloride 44 is both tertiary
and propargylic and is suitably poised for â-elimination. A wider
range of nucleophiles can be used with similar reactivity.
However, soft nucleophiles such as alkyl cuprates give SN2′
attack at the terminal acetylene to give diastereomeric allenes
which is consistent with results published by Ohno and
co-workers.34
a Method A: p-R3-phenol (2.2 equiv), DBU (2.2 equiv), CuOAc (2.5
mol %), toluene. bYield represents combined yield of inseparable ether and
c
d
pyrrole. Method B: p-R3-phenol (2 equiv), TBD (2 equiv), toluene. No
pyrrole observed.
(Chart 2), in which the yield of 26 was more than tripled with
the optimized conditions.
The diastereomeric silyloxy aziridine 25 was reacted under
the same conditions to probe the stereoselectivity of the reaction.
This (S,S)-silyloxy aziridine underwent ring opening with
inversion to give only one diastereomer (Chart 2, 35). The
stereochemistry of aziridines 23 and 25 were supported by NOE
studies of both and a crystal structure of 25. The structure of
ether 26 was verified by X-ray crystallography confirming
inversion of configuration. These results showed that the ring
opening reaction is stereospecific, thus making it useful in
organic synthesis as any desired stereochemistry of the quater-
nary center may be realized by changing the configuration at
C2.
To make quaternary-â-substituted-R-amino acids, an aziridine
with an ester substituent at C3 was synthesized (22, Scheme
2). This aziridine would further probe the tolerance for sub-
stituent modification at C3. Using the optimized conditions, a
study of the scope of benzyl carboxylate aziridine 22 ring
opening was completed (Chart 3). Yields using TBD were also
high, ranging from 65 to 91%. The benzyl group may be directly
removed from these substrates to yield quaternary â-phenoxy-
R-amino acids which are not easily formed by other methods.
The present transformation allows for a stereo- and regioselec-
tive formation of these amino esters in high yield.
Scope of Nucleophile. To gauge the reactivity as well as to
explore the synthetic utility of these aziridines, other nucleo-
(33) Wu, J.; Hou, X. L.; Dai, L. X. J. Org. Chem. 2000, 65, 1344.
9
J. AM. CHEM. SOC. VOL. 129, NO. 46, 2007 14467

A R T I C L E S
Forbeck et al.
Scheme 6. Study of the Scope of Nucleophiles in the Ring Opening Reaction
Scheme 7. Synthesis and Ring Opening of Ethyl Aziridine 46
Conclusions
Mechanistic Insight. Literature precedent suggested that
propargyl substitution of alkyl halides occurs through an allene-
carbenoid intermediate.35,36 To probe the mechanism of the
aziridine ring opening reaction, an aziridine with alkyl substitu-
tion at C2 was prepared. 2-Ethyl silyloxy aziridine 46 was
synthesized using the same approach as with the alkynyl
aziridines (Scheme 7). The alkyne of tertiary alcohol 17 was
reduced to the ethyl group via hydrogenation. Subsequent
removal of the Boc and N,O-acetal groups followed by
formation of the N-nosyl derivative gave 45 in 75% yield.
Protection of the primary alcohol as its tert-butyl dimethylsilyl
ether in 99% yield followed by Mitsunobu ring closure gave
the aziridine 46 in 88% yield.
Aziridine 46 underwent regio- and stereoselective ring
opening to give ether 47 in 70% yield over 5 days. This result
showed that the reaction can take place in the absence of an
alkyne and still at the more hindered center, albeit with longer
reaction time, without the possibility of forming an allene-
carbene intermediate. This result will allow for a much broader
range of utility in that the reaction is no longer limited to alkynyl
aziridines.
A regio- and stereoselective aziridine ring opening reaction
has been investigated. For all of the trisubstituted aziridines that
were tested, there is a regiochemical preference for attack at
C2, the more substituted carbon. The regioselectivity did not
require the carboxamide as replacing the group with a lesser
electron-withdrawing substituent did not diminish this selectiv-
ity. This selectivity was unexpected since C2 appeared to be
more sterically hindered and was, therefore, expected to show
diminished activity for nucleophilic attack. The formation of
an allene-carbene intermediate to direct this regioselectivity is
not consistent with the ring opening of ethyl aziridine 46, which
displayed the same regiochemical preference.
Because these results were not anticipated, low-level molec-
ular modeling was completed for aziridines 23, 25, and 46 for
easier comparison.37 These computational results showed that
in both the alkyl and alkynyl aziridines the C2-N bond was
longer than the C3-N bond. Additionally, there is a partially
positive charge on C2. The crystal structure of aziridine 25
further established that the distance of the C2-N bond is 1.522
Å while the C3-N bond is 1.496 Å demonstrating that the C2-N
bond is in fact the weaker bond (Figure 1). Furthermore, the
ethynyl-C2-methyl bond angle is greater than that of a normal
tetrahedral carbon (114°), a property that may increase regi-
oselectivity and decrease steric hindrance at that carbon.38
(34) Ohno, H.; Toda, A.; Fujii, N.; Takemoto, Y.; Tanaka, T.; Ibuka, T.
Tetrahedron 2000, 56, 2811.
(35) Hennion, G. F.; Nelson, K. W. J. Am. Chem. Soc. 1957, 79, 2142.
(36) Shiner, V. J.; Humphrey, J. S. J. Am. Chem. Soc. 1967, 89, 622.
(37) Modeling calculations were completed at the level of: HF/3-21G//AM1.
(38) For a discussion of nucleophilic aziridine ring opening reactions, see:
Stamm, H. J. Prakt. Chem. 1999, 341, 319 and references therein.
Figure 1. X-ray structure of aziridine 25.
9
14468 J. AM. CHEM. SOC. VOL. 129, NO. 46, 2007

Quaternary Centers from Trisubstituted Aziridines
A R T I C L E S
Stereospecificity was demonstrated in all ring opening
reactions. In each reaction, the ring opening proceeded with
inversion of configuration at C2. This inversion was noted in
reactions with a variety of nucleophiles. The results suggest that
the stereo- and regiospecificity is determined by inherent
properties of the aziridine rather than properties of the nucleo-
philes.
Contrary to previously observed results, it was found that
the copper catalyst is not required for reactivity. The most
suitable base for this reaction is TBD. Mild reaction conditions
and predictable stereo- and regiospecificity make this aziridine
ring opening well-suited for application to the synthesis of
complex natural products.
0515443. We also thank the NIH (CA-40081), Wyeth Research,
and the University of Pennsylvania (Research Foundation) for
financial support.
Supporting Information Available: Complete reference 20,
experimental procedures, spectroscopic and analytical data for
new compounds, 1H, 13C, and NOE difference spectra of
aziridines 1, 2, 22, 23, 25, 46, 1H and 13C spectra of ring opened
products and side products 16, 30-35, 36-41, 42-44, and 47,
and crystallographic files of compounds 25, 26, 27, 30, 31, 33,
37, and 44. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This material is based upon work sup-
ported by the National Science Foundation under Grant No.
JA0758077
9
J. AM. CHEM. SOC. VOL. 129, NO. 46, 2007 14469