Diastereocontrolled Synthesis of trans- and cis-meso-Cyclopentene Aziridines

Article abstract of DOI:10.1021/ol0259387

(Equation Presented) The synthesis of novel substituted meso-aziridines is described: aziridination of 4-tert-butyldiphenylsilyloxy-cyclopent-1-ene is trans selective using Cu(I)/PhI=NSO₂Ar and cis selective using PhNMe₃⁺B

Full text of DOI:10.1021/ol0259387

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1923-1926
Diastereocontrolled Synthesis of trans-
and cis-meso-Cyclopentene Aziridines
,‡
Darren Caine,† Peter O’Brien,* and Clare M. Rosser‡
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, U.K., and
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road,
SteVenage SG1 2NY, U.K.
paob1@york.ac.uk
Received March 28, 2002
ABSTRACT
The synthesis of novel substituted meso-aziridines is described: aziridination of 4-tert-butyldiphenylsilyloxy-cyclopent-1-ene is trans selective
using Cu(I)/PhIdNSO Ar and cis selective using PhNMe3+Br3-/Chloramine-T.
2
The synthesis of enantiomerically enriched chiral building
blocks via asymmetric desymmetrization of meso cyclic and
acyclic epoxides is a well-established and widely studied
method in organic synthesis.1,2 In contrast, much less
attention has been devoted to the asymmetric desymmetri-
zation of meso-aziridines. The following are the only
examples reported to date: (i) Scheffold and da Zhang’s
Vitamin B12-mediated rearrangement of N-acyl aziridines to
allylic amides with up to 95% enantioselectivity;3 (ii)
Jacobsen et al.’s ring opening of N-alkyl aziridines with Me3-
SiN3 in the presence of a Schiff base-chromium complex
to give azido amines in up to 94% ee;4 (iii) Oguni and co-
workers’ reaction of thiols with N-acyl aziridines and a
diethyl zinc-tartrate catalyst to generate amino sulfides in
up to 93% ee;5 (iv) Mu¨ller and Nury’s use of a Schiff base-
copper catalyst to promote the addition of a Grignard reagent
to N-sulfonyl aziridines with up to 91% enantioselectivity;6
and (v) Mu¨ller and Nury’s desymmetrization of N-sulfonyl
aziridines using an alkyllithium and (-)-sparteine.6
With this current interest in desymmetrization reactions
of meso-aziridines, we decided to investigate some methods
for the direct conversion of alkenes into substituted meso
cyclic aziridines (Scheme 1). There are a handful of reports
Scheme 1
† GlaxoSmithKline.
on the synthesis of substituted meso-aziridines. For example,
Zalkow and Hill, Gassman and Schaffhausen, and Ganem
et al. have all made contributions in this area, but their
approaches are not general.7 In addition, we have reported
the synthesis of meso-cyclohexene aziridines trans- and cis-3
‡ University of York.
(1) For reviews, see: Hodgson, D. M.; Gibbs, A. R.; Lee, G. P.
Tetrahedron 1996, 52, 14361. Willis, M. C. J. Chem. Soc., Perkin Trans.
1 1999, 1765. Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421.
(2) For recent examples of this strategy in synthesis, see: Hodgson, D.
M.; Cameron, I. D. Org. Lett. 2001, 3, 441. de Sousa, S. E.; O’Brien, P.;
Pilgram, C. D. Tetrahedron Lett. 2001, 42, 8081.
(3) da Zhang, Z.; Scheffold, R. HelV. Chim. Acta 1993, 76, 2602.
(4) Li, Z.; Ferna´ndez, M.; Jacobsen, E. N. Org. Lett. 1999, 1, 1611.
(5) Hayashi, M.; Ono, K.; Hoshimi, H.; Oguni, N. Tetrahedron 1996,
52, 7817.
(6) Mu¨ller, P.; Nury, P. HelV. Chim. Acta 2001, 84, 662.
(7) Zalkow, L. H.; Hill, R. H. Tetrahedron 1975, 31, 831. Gassman, P.
G.; Schaffhausen, J. G. J. Org. Chem. 1978, 43, 3241. Schoenfeld, R. C.;
Lumb, J.-P.; Ganem, B. Tetrahedron Lett. 2001, 42, 6447.
10.1021/ol0259387 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/30/2002

by epoxidation of the corresponding aziridino cyclohexene
(Scheme 2).8
stereochemistry of the aziridines was established by synthesis
from an epoxide of known stereochemistry (vide infra).
The mechanism of the Sharpless aziridination involves the
initial formation of a bromonium ion and subsequent attack
by a nitrogen source before ring closure to form the
aziridine.8 Thus, we anticipated that cis-aziridines would be
the major diastereoisomers obtained via preferred formation
of the bromonium ion trans to the OR substituent. As can
be seen from the results in Table 1, this was indeed the case
with cis-aziridines predominating (around 70:30 cis:trans
diastereoselectivity). Surprisingly, there was little change in
the diastereoselectivity when varying the size of the sub-
stituent from OH to OTBDPS (compare entries 1 and 4 in
Table 1). From a synthetic point of view, we note that the
hydroxyl-substituted aziridines cis- and trans-8 were formed
in a high 86% yield (Table 1, entry 1) but were not separable
by chromatography, and the total yield of aziridines increased
as the stability of the hydroxyl protecting group increased
to a maximum 96% yield of aziridines cis- and trans-11
(Table 1, entry 4, TBDPS protecting group). Thus, a
synthetically useful cis selective aziridination result has been
achieved: starting from alkene 7 (TBDPS protecting group),
Sharpless aziridination afforded a 59% isolated yield of
aziridine cis-11 (Table 1, entry 4).
Scheme 2
To develop a general route to substituted meso-aziridines,
our starting point and the subject of this Letter is a study of
the aziridination of free and protected hydroxy substituted
cyclopentenes 1 as a way of preparing meso-aziridines trans-
and cis-2 (Scheme 1). Two routes for direct aziridination of
alkenes have been utilized in the present study: (i) reaction
involving the use of Chloramine-T (TsNClNa‚3H2O) and
phenyltrimethylammonium tribromide, introduced by Sharp-
less et al.,9 and (ii) reaction using an iodinane PhIdNSO2-
Ar and copper(I) or copper(II) salts, introduced by Evans et
al.10 and developed further by Andersson and co-workers.11
Although the diastereoselectivity of functionalizing alkenes
has been widely studied for many reactions (e.g., epoxidation,
dihydroxylation, cyclopropanation),12 it is interesting to note
that there are only a few examples of the diastereoselective
aziridination of alkenes.13,14 The main aim of our study was
the discovery of conditions and/or substrates for the dia-
stereocontrolled preparation of each of the aziridines trans-2
and cis-2 from alkenes 1.
The relative stereochemistry of the aziridines was estab-
lished as outlined in Scheme 4. Starting from epoxide trans-
Scheme 4
A range of substituted hydroxyl-protected cyclopentenes
5-7 were readily prepared by standard protection of known15
3-cyclopenten-1-ol 4. All four cyclopentenes 4-7 were
aziridinated under standard Sharpless conditions (1.1 equiv
of commercial Chloramine-T,16 10 mol % of phenyltri-
methylammonium tribromide, acetonitrile, room temperature,
16 h) (Scheme 3), and the results are presented in Table 1.
Scheme 3
12 of known17 stereochemistry, ring opening with sodium
azide gave azido alcohol 13, which was converted into
aziridine cis-10 by treatment with triphenylphosphine and
(10) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc.
1994, 116, 2742.
(11) So¨ndergren, M. J.; Alonso, D. A.; Bedekar, A. V.; Andersson, P.
G. Tetrahedron Lett. 1997, 38, 6897.
1
The degree of diastereoselectivity was established by H
(12) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
NMR spectroscopy on the crude product mixtures, and the
aziridines were isolated by chromatography. The relative
1307.
(13) For examples of diastereoselective aziridination reactions using PhId
NTs, see: Hudlicky, T.; Tian, X.; Ko¨nigsberger, K.; Maurya, R.; Rouden,
J.; Fan, B. J. Am. Chem. Soc. 1996, 118, 10752. White, R. D.; Wood, J. L.
Org. Lett. 2001, 3, 1825.
(14) For examples of diastereoselective aziridination reactions not
involving iodinanes, see: Fioravanti, S.; Luna, G.; Pellacani, L.; Tardella,
P. A. Tetrahedron 1997, 53, 4779. Atkinson, R. S.; Kelly, B. J. Chem.
Commun. 1998, 624.
(8) O’Brien, P.; Pilgram, C. D. Tetrahedron Lett. 1999, 40, 8427.
(9) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B. J.
Am. Chem. Soc. 1998, 120, 6844. Gontcharov, A. V.; Liu, H.; Sharpless,
K. B. Org. Lett. 1999, 1, 783. For a different ammonium salt used in the
same type of aziridination protocol, see: Ali, S. I.; Nikalje, M. D.; Sudulai,
A. Org. Lett. 1999, 1, 705.
1924
Org. Lett., Vol. 4, No. 11, 2002

Table 1. Diastereoselective Aziridination of Alkenes 4-7 Using Sharpless Conditions
entry
R
alkene
aziridine
trans:cisa
total yield (%)b
yield of trans (%)c
yield of cis (%)c
1
2
3
4
H
TES
TBS
TBDPS
4
5
6
7
8
9
10
11
29:71
31:69
35:65
37:63
86d
58
79
96
22
31
37
36
48
59
a By 1H NMR spectroscopy on the crude product mixture. b Total isolated yield of trans- and cis-aziridines after chromatography. c Isolated yield of pure
trans- or cis-aziridine after chromatography. d An 86% yield of a 28:72 mixture of trans- and cis-8 after chromatography.
then p-toluenesulfonyl chloride. Deprotection of the TBS
group in aziridine cis-10 then gave hydroxy aziridine cis-8.
Further protection or deprotection reactions, together with
introduction of a p-nitrobenzenesulfonyl substitutent on
nitrogen in the sequence shown in Scheme 4, enabled us to
prove the stereochemistry of all of the aziridines depicted
in this paper. Furthermore, our results have led to a useful
1H NMR spectroscopy correlation, which allows quick
identification of the relative stereochemistry of aziridines of
the general structure 2.18
The Sharpless aziridination route was only moderately cis
diastereoselective, affording around 70:30 mixtures of cis-
and trans-aziridines (see Table 1). Consequently, we inves-
tigated an alternative approach for the synthesis of cis-
aziridines as outlined in Scheme 5. Oxidation of the 72:28
NMR spectroscopy on the crude product), which was isolated
in 80% yield. Presumably, the hydride attacks the carbonyl
group from the least hindered exo face of the bowl-shaped
keto aziridine 14. This two-step oxidation-reduction se-
quence is the best approach to cis-aziridines.
In developing a diastereoselective entry into the corre-
sponding trans-aziridines, we anticipated using an iodinane
(e.g., PhIdNTs) in the presence of copper(I) or copper(II)
salts since there are two reports of aziridination on the least
hindered face of an alkene using these conditions.12 However,
to obtain high yields in Evans’ aziridinations, it is necessary
to use either a large excess of the alkene or very dilute
conditions.9 Instead, we were attracted to the use of
p-NO2C6H4SO2NdIPh in the presence of Cu(MeCN)4ClO4,
as described by Andersson et al.,10 for three reasons: (i)
Andersson reported much improved yields when using
p-NO2C6H4SO2NdIPh compared with using PhIdNTs;10 (ii)
the p-nitrobenzenesulfonyl group can be conveniently depro-
tected using thiols, as reported by Fukuyama et al.;20 and
(iii) p-nitrobenzenesulfonyl-substituted aziridines show in-
creased reactivity to nucleophilic opening,21 which could be
important in subsequent desymmetrization reactions. Hence,
all four cyclopentenes 4-7 were aziridinated under Andersson
conditions (1.5 equiv of p-NO2C6H4SO2NdIPh, 5 mol % of
Cu(MeCN)4ClO4, acetonitrile, room temperature, 16 h)
(Scheme 6), and the diastereoselectivity was ascertained in
Scheme 5
mixture of hydroxy aziridines cis- and trans-8 (obtained in
a high 86% yield by Sharpless aziridination of alcohol 4)
using Dess-Martin periodinane19 gave keto aziridine 14 in
quantitative crude yield. Although potentially prone to
â-elimination, keto aziridine 14 proved to be a sufficiently
stable compound (provided that it was not subjected to silica
gel). Reduction of the crude keto aziridine 14 with sodium
borohydride in methanol at 0 °C then gave a single
Scheme 6
1
diastereoisomeric hydroxy aziridine cis-8 (as judged by H
(15) Crandall, J. K.; Banks, D. B.; Coyler, A.; Watkins, R. J.; Arrington,
J. P. J. Org. Chem. 1968, 33, 423.
(16) All of the aziridination reactions using Sharpless conditions reported
in this paper have been carried out with the commercially available trihydrate
of Chloramine-T (TsNClNa‚3H2O).
a fashion analogous to that described previously. The results
are shown in Table 2.
Using the Andersson conditions, the highest combined
yields of diastereoisomeric aziridines were obtained with a
(17) Asami, M. Bull. Chem. Soc. Jpn. 1990, 63, 1402.
(18) For aziridines trans-2, the diastereotopic CHAHB appear at δH 2.42-
2.17 and 1.81-1.63; for aziridines cis-2, the diastereotopic CHAHB appear
at δH 2.09-2.03 and 1.99-1.89. That is, aziridines trans-2 have “more
separated” diastereotopic CHAHB groups than aziridines cis-2. Furthermore,
for aziridines trans-2 (R*H), the CHO signal appears as a quintet (J ) 7.5
Hz) at δH 4.06-4.17; for aziridines cis-2 (R*H), the CHO signal appears
as a broad triplet (J ) 6.5-7.0 Hz) at δH 4.36-4.41.
(20) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373. Nihei, K-i.; Kato, M. J.; Yamane, T.; Palma, M. S.; Konno, K. Synlett
2001, 1167.
(21) Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J. Tetrahedron
Lett. 1997, 30, 5253.
(19) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
Org. Lett., Vol. 4, No. 11, 2002
1925

Table 2. Diastereoselective Aziridination of Alkenes 4-7 Using Andersson Conditions
entry
R
alkene
aziridine
trans:cisa
total yield (%)b
yield of trans (%)c
yield of cis (%)c
1
2
3
4
H
TES
TBS
TBDPS
4
5
6
7
15
16
17
18
30:70
84:16
86:14
87:13
67
34d
40
64
27
40
53
7
0
11
a By 1H NMR spectroscopy on the crude product mixture. b Total isolated yield of trans- and cis-aziridines after chromatography. c Isolated yield of pure
trans- or cis-aziridine after chromatography. d In this case, 3.0 equiv of NsNdIPh were used.
free hydroxyl group (67% yield, Table 2, entry 1) and the
robust TBDPS hydroxyl protecting group (64% yield, Table
2, entry 4). As expected, steric factors ensured that trans-
aziridines were the major diastereoisomers with the silyl-
protected alkenes 5-7, although the diastereoselectivity was
essentially independent of the steric size of the silyl group
(Table 2, entries 2-4). In this way, a synthetically useful
trans selective aziridination has been accomplished: starting
from alkene 7 (TBDPS protecting group), Andersson aziri-
dination afforded a 53% yield of aziridine trans-11 (Table
2, entry 4). Interestingly, we found that aziridination of
hydroxy alkene 4 was cis diastereoselective: an inseparable
70:30 mixture of aziridines cis- and trans-8 was generated
in a good 67% yield (Table 2, entry 1). Even though this is
the sterically least demanding substituent, the cis diastereo-
selectivity is still surprising. We speculate that this is an
example of a transition metal-catalyzed hydroxyl-directed
aziridination that clearly merits further investigation.22
In summary, we report a range of diastereoselective
aziridination reactions of alkenes in which it is possible to
control the sense of the diastereoselectivity by changing the
reaction conditions. For example, starting from alkene 7, it
is possible to obtain either aziridine cis-11 (59% yield) via
a Sharpless protocol or aziridine trans-18 (53% yield) via
an Andersson protocol. Alternatively, reduction of keto
aziridine 14 furnishes an 80% yield of hydroxy aziridine cis-
8. Thus, via a series of different reaction sequences, reagents,
and protecting groups, we have shown that it is possible to
synthesize the previously unknown substituted meso-aziri-
dines 2. Convenient access into these types of substituted
meso-aziridines should now facilitate studies into their
asymmetric desymmetrization.
Acknowledgment. We thank the EPSRC and Glaxo-
SmithKline for a CASE award (to C.M.R.).
Supporting Information Available: Full details on the
synthesis and characterization of trans and cis isomers of
compounds 8-11, cis and trans isomers of compounds 15-
18, and compound 14. This material is available free of
charge via the Internet at http://pubs.acs.org.
(22) For an example of a hydroxyl-directed aziridination, see: Atkinson,
R. S.; Kelly, B. J. J. Chem. Soc., Perkin Trans. 1 1989, 1515.
OL0259387
1926
Org. Lett., Vol. 4, No. 11, 2002