Base-promoted elaboration of aziridines

Article abstract of DOI:10.1016/S0040-4020(02)00729-9

The base-promoted isomerization of aziridines to allyl amines is still an almost unknown reaction. However, the use of superbasic reagents has shown to be able to promote a regio- and stereoselective conversion of monocyclic and bicyclic sulfonyl aziridin

Full text of DOI:10.1016/S0040-4020(02)00729-9

Tetrahedron 58 (2002) 7153–7163
Base-promoted elaboration of aziridines
*
Alessandro Mordini, Francesco Russo, Michela Valacchi, Lorenzo Zani,
Alessandro Degl’Innocenti and Gianna Reginato
Dipartimento di Chimica Organica “U. Schiff”, Istituto di Chimica dei Composti Organometallici, via della Lastruccia 13,
50019 Sesto Fiorentino, Firenze, Italy
Received 17 May 2002; accepted 23 May 2002
Abstract—The base-promoted isomerization of aziridines to allyl amines is still an almost unknown reaction. However, the use of
superbasic reagents has shown to be able to promote a regio- and stereoselective conversion of monocyclic and bicyclic sulfonyl aziridines.
Moreover, the use of alkoxy substituted aziridines opens new routes to non-natural a- and b-amino acids. q 2002 Elsevier Science Ltd. All
rights reserved.
Aziridines are valuable intermediates in organic synthesis
owing to their easy availability and versatility. Their high
ring tension (26 kcal/mol) coupled with the polarization of
the C–NR bond, originates their rich reactivity as demon-
strated by the great number of synthetic elaborations
reported so far.1–5 In analogy with oxiranes, nucleophilic
ring-openings are certainly the most widely studied
reactions of aziridines. There is however a notable
difference between the two heterocycles concerning their
reactivity with bases. While a-lithiation is well-known6 for
both classes of compounds, b-deprotonation leading to
ring-opening and isomerization is widely studied in the
oxirane series7 but almost unknown for aziridines.
metrization of epoxycycloalkanes with chiral lithium
amides, even in catalytic amounts.23,25,26
Despite this large array of information on oxiranes, the base-
promoted b-elimination of aziridines has been almost
ignored until very recently. Probably the first example of
aziridine–allylamine conversion was reported by Scheffold
in 199327 by using cob(I)alamin as a catalyst although the
reaction was very slow and took place actually through an
addition–elimination pathway. The first true base-promoted
isomerization was published in 2001 by Mu¨ller28 who
described the desymmetrization of the meso-sulfonyl
aziridine 1 with sec-butyllithium/sparteine. Unfortunately,
under these conditions, the aziridine isomerization was not
regioselective yielding both a- and b-deprotonation (to the
enamine 2 and allylamine 3 respectively, Scheme 2) and the
enantioselectivity in the formation of the allylamine 3 was
quite low.
By treatment with organolithium reagents or lithium
amides, epoxides are known to be converted into allylic
alcohols through a syn-periplanar, b-elimination process8,9
(Scheme 1). The reaction lacks some selectivity because of
several alternative pathways which can be minimized10 by
using superbasic reagents11,12 such as the lithium diiso-
propyl amide/potassium tert-butoxide mixture.13
Asymmetric variants of this reaction have also been the
subject of many recent investigations.14–17 Good levels of
enantioselectivity have been achieved18–24 in the desym-
Scheme 2.
Scheme 1.
Keywords: aziridines; superbase; rearrangement; allyl amine; amino acid.
*
Corresponding author. Tel.: þ39-55-4573555; fax: þ39-55-4573531; e-mail: alessandro.mordini@unifi.it
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00729-9

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A. Mordini et al. / Tetrahedron 58 (2002) 7153–7163
In addition, O’Brien29 showed that the meso-aziridino
cyclohexene oxide 4 underwent rearrangement on the
oxirane ring only (to the aziridino allylic alcohol 5, Scheme
3) and that in the absence of the epoxide ring no reaction
occurred when employing unactivated bases such as lithium
diisopropylamide. The reactivity of aziridines with bases
seems then much lower in comparison with the analogous
oxygenated heterocycles.
Figure 1.
In a first series of experiments we have examined the
superbase promoted isomerization of 7-azabicyclo[4.1.0]-
heptanes 6a–e to the corresponding allylic amines as a
function of various reaction conditions and of activating
groups on nitrogen (Fig. 1).
Scheme 3.
Benzenesulfonyl, tert-butoxycarbonyl (Boc) and pivaloyl
aziridines (6b, 6c and 6d, respectively) have been obtained
via the oxirane elaboration while the tosyl aziridine 6a has
been easily prepared by direct aziridination with the
Komatsu method.44 The trifluoroacetyl aziridine 6e cannot
be prepared by the use of these standard procedures owing
to its high propensity to undergo ring-opening under these
reaction conditions. It has been obtained however using a
modified method starting from 2-aminocyclohexanol
through selective trifluoroacetylation of the amino group,
mesylation of the hydroxy substituent and ring closure by
treatment with lithium hexamethyldisilazide (Scheme 6).
This lack of information prompted us to extend our
experience on the base-promoted isomerization of oxi-
ranes30–37 to the aziridine series.
The aziridine ring can be obtained in a number of ways1,3
both as racemic and enantioenriched compounds. The most
straightforward method is the direct aziridination reaction
with chloramine-T and analogues (Scheme 4), which can be
performed according to several different procedures, to
access racemic sulfonyl aziridines. Copper,38,39 palladium40
and iron41,42 catalysts in addition to substoichiometric
amounts of bromine43 and iodine44,45 have been used in the
aziridination with chloramine-T or bromamine-T.
The N-substituted aziridines 6a–e have been then submitted
to treatment with the superbasic mixtures butyllithium/
potassium tert-butoxide (LICKOR) or lithium diisopropyl-
amide/potassium tert-butoxide (LIDAKOR).
While the two sulfonyl aziridines 6a and 6b undergo a
regioselective rearrangement to the corresponding allylic
sulfonyl amide 7a and 7b by treatment with LIDAKOR both
in pentane at 258C and in THF at 2508C, the Boc- and
pivaloyl aziridines 6c and 6d are simply deprotected to
7-azabicyclo[4.1.0]heptane 8 (Scheme 7).
Scheme 4.
An alternative, longer but usually high yielding method, is
the three-step procedure which leads to N–H aziridines
from alkenes through epoxidation, opening with azide and
reductive ring closure with triphenylphosphine3,5,46
(Scheme 5).
In this case, most likely, the base acts as a nucleophile on the
carbonyl group, thus inducing the C–N bond breaking at a
later stage.47 It is worth noting that the rearrangement of the
Scheme 5.
Scheme 6.
Scheme 7.

A. Mordini et al. / Tetrahedron 58 (2002) 7153–7163
7155
sulfonyl aziridine 6a is highly regioselective, the allyl amide
being the only detectable product, while the use of simple
lithium amides gives a mixture of the two isomeric amines28
as previously discussed.
9-Tosyl-9-azabicyclo[6.1.0]nonane 12 shows an interesting
reactivity with superbases. When treated with LIDAKOR in
pentane at room temperature a completely regioselective
conversion to the 1-N-tosylamino[3.3.0]octane 17 in a 64%
yield is observed. If the reaction is conducted at lower
temperature in THF with LICKOR, then a mixture of 17 and
the N-tosyl allyl amine 18 is obtained (Scheme 10). At
2208C still the bicyclic amine is preferred over the allylic
one with a 80:20 ratio while at 2508C, an almost equal
amount (45:55) of the two amines is formed in a 60%
overall yield.
The trifluoroacetyl substituted substrate 6e reacts even with
non-activated lithium amides to yield the diamine 9,
probably derived from initial deprotection to the lithio
aziridine 10 followed by nucleophilic ring opening of a
second activated aziridine molecule (Scheme 8).
Scheme 10.
The behavior in pentane again reflects that recently reported
by Mu¨ller28 but is in sharp contrast with the reactivity of
the corresponding oxirane which gives exclusively the
allylic alcohol when treated with superbases even in non-
polar solvents.10 On the other hand, it is known that
cyclooctenoxide 19 is selectively converted into cyclo-
octen-2-enol 21 when lithium amides in the presence of
HMPA are used48 and into bicyclo[3.3.0]octan-1-ol 20 if the
lithium amide is employed in ether/hexane (Scheme 11).
Scheme 8.
According to these initial investigations, the tosyl group is
certainly the best one for the purpose of promoting a base-
induced rearrangement. Tosyl aziridines are easily accessed
as shown above and react with high regioselectivity and
good yields with mixed metal bases. We have then prepared
a series of N-tosyl aziridines 11–15 (Fig. 2) making use of
the Komatsu44 protocol, and we have submitted all of them
to treatment with superbasic reagents.
Scheme 11.
This has been attributed to a b-elimination process in polar
medium where more reactive monomeric species are more
likely to be present and to a a-metalation in the presence of
more aggregated lithium species.9,49 Our results with the
tosyl-aziridine derived from cyclooctene seem to confirm
this hypothesis and indicate that, in this particular case, an
a-elimination process takes place even with superbases in
pentane.
Figure 2.
6-Tosyl-6-azabicyclo[3.1.0]hexane 11 behaves similarly to
the homologue 6a giving the corresponding allyl tosylamide
16 even if in lower yields (Scheme 9). Both aziridines show
a reactivity which is similar to the corresponding oxiranes
but require more drastic reaction conditions; while oxiranes
react with superbases even in THF at low temperature,10
aziridines give usually the best results when treated in
pentane at room temperature.
The monocyclic symmetrical aziridine 13 is also regio- and
stereoselectively converted into the corresponding allylic
amine 22 by treatment with LIDAKOR in pentane at room
temperature (Scheme 12).
Scheme 12.
It is worth noting that 22 is obtained as a pure E-isomer
while the LIDAKOR promoted isomerization of the
corresponding oxirane affords a 1:2, Z/E mixture of allylic
Scheme 9.

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A. Mordini et al. / Tetrahedron 58 (2002) 7153–7163
The required conditions appear then to favor an equi-
libration towards the more stable internal double bond.
The presence of additional functional groups on the
aziridine substrates has been also investigated. Aryl,
alkylaryl and alkoxy substituted aziridines 25–27 (Fig. 3)
have been prepared either by direct aziridination of the
corresponding alkene (25) or via epoxide elaboration (26
and 27) in an enantioenriched form by using the Sharpless
asymmetric epoxidation of the corresponding allylic
alcohols (94% ee from E-4-phenyl-2-butenol and 84% ee
from E-2-octenol, respectively).
Scheme 13.
While the aziridine derived from dihydronapthalene 25
upon treatment with superbasic reagents shows only
products deriving from a nucleophilic ring-opening, aziri-
dines 26 and 27 give a more synthetically useful result. The
benzyl substituted substrate 26 undergoes deprotonation on
the benzylic methylene group thus affording the allyl amino
ether 28 with perfect regio- and stereocontrol. Aziridine 27,
on the other hand, is regioselectively deprotonated only on
the methylene adjacent to the alkoxy substituent thus giving,
after quenching with water, the amino vinyl ether 29 as a
pure E-isomer50 (Scheme 14). Allyl amines 28 and 29 have
the same optical purities than those of starting aziridines
thus showing a perfect sterocontrol during the isomerization
step.
Figure 3.
alcohols.10 The higher selectivity showed by tosyl aziridines
may be due to an increased steric crowding caused by the
presence of the large tosyl group on nitrogen in the syn-
periplanar arrangement required for the elimination.7
Both products are very useful intermediates in non-natural
amino acid synthesis; 28 can be considered as a precursor of
the b,g-unsaturated a-amino acid styrylglycine 30 while 29
can be viewed as b-amino aldehyde 31 equivalent and thus
precursor of b-amino acids. Indeed, such a transformation is
easily accomplished by simple removal of the methoxy-
methyl group to the aldehyde 32 and subsequent oxidation
with periodic acid in the presence of a catalytic amount
of chromium oxide to the N-tosyl b-amino acid 33
(Scheme 15).
Both Z- and E-aziridines 14 and 15 behave exactly in the
same way affording a mixture of the two tosyl allyl amines
23 and 24 in the same ratio (33:67) with a 60% overall yield
(Scheme 13).
The observed preference for methylene deprotonation is
quite surprising if one compares it again with what found in
the isomerization of oxiranes. In the latter case indeed, only
the allylic alcohol with the terminal double bond is formed,
deriving from proton abstraction from the kinetically more
acidic methyl group. However, it must be observed that
oxirane isomerization with superbases is always carried out
in THF at low temperature while aziridine rearrangement
occurs only in hydrocarbon solvents at room temperature.
Presently, superbases offer then a quite unique chance to
perform the aziridine–allylamine isomerization. Such
reaction opens new routes and new fields of investigations
in comparison with what already well established for
oxiranes. Moreover, functionalized aziridines may give
Scheme 14.
Scheme 15.

A. Mordini et al. / Tetrahedron 58 (2002) 7153–7163
7157
access to a wide variety of amino derivatives of synthetic
interest such as amino acids.
m); 7.29–7.33 (2H, m); 3.32 (2H, m); 2.43 (3H, s); 1.87–
1.99 (2H, m); 1.25–1.68 (4H, m). 13C NMR (CDCl3,
50 MHz) d: 144.0; 136.0; 129.6; 127.5; 46.7; 26.9; 21.6;
19.5.
1. Experimental
1.3.2. N-p-Toluenesulfonyl-7-azabicyclo[4.1.0]heptane
6a.53 Purification: eluent petroleum ether/ethyl acetate 9:2;
yield: 56%. 1H NMR (CDCl3, 200 MHz) d: 7.79–7.83 (2H,
m); 7.30–7.34 (2H, m); 2.96 (2H, m); 2.43 (3H, s); 1.78
(4H, m); 1.30 (4H, m). 13C NMR (CDCl3, 50 MHz) d:
143.9; 135.8; 129.5; 127.5; 39.8; 22.8; 21.6; 19.4. MS (m/z,
%): 155(1); 96(100); 91 (23); 69(50);67 (10); 65(19); 55 (12).
1.1. General procedures
Air- and moisture-sensitive compounds were stored in
Schlenk tubes or in Schlenk burettes. They were protected
by and handled under an atmosphere of 99.99% pure
nitrogen. Ethereal extracts were dried with sodium sulfate.
Purifications by flash column chromatography51 were
performed using glass columns (10–50 mm wide); silica
gel 230–400 mesh was chosen as stationary phase (15 cm
high), with an elution rate of 5 cm/min. Nuclear magnetic
resonance spectra of hydrogen nuclei were recorded at
200 MHz. Chemical shifts were determined relative to the
residual solvent peak (CHCl3: 7.26 ppm). Coupling con-
stants (J ) are measured in Hz. Coupling patterns are
described by abbreviations: s (singlet), d (doublet), t
(triplet), q (quartet), quint (quintet), dd (doublet of a
doublet), m (multiplet), bs (broad singlet). Nuclear magnetic
resonance spectra of carbon-13 nuclei were recorded at
50.3 MHz. Chemical shifts were determined relative to the
residual solvent peak (CHCl3: 77.0 ppm). Mass spectra were
obtained at a 70 eV ionization potential.
1.3.3. N-p-Toluenesulfonyl-9-azabicyclo[6.1.0]nonane
12.53 Purification: eluent petroleum ether/diethyl ether 5:2;
yield: 33%. 1H NMR (CDCl3, 200 MHz) d: 7.79–7.83
(2H, m); 7.30–7.34 (2H, m); 2.77 (2H, m); 2.44 (3H, s);
1.97–2.04 (2H, m); 1.25–1.75 (10H, m).
1.3.4. trans-N-p-Toluenesulfonyl-2,3-dipropylaziridine
13.53 Purification: eluent petroleum ether/ethyl acetate 9:1;
yield: 42%. 1H NMR (CDCl3, 200 MHz) d: 7.81–7.85 (2H,
m); 7.29–7.33 (2H, m); 2.64 (2H, q, J¼4.9 Hz); 2.43 (3H,
s); 1.50–1.80 (4H, m); 1.25–1.45 (4H, m); 0.90 (6H, m).
13C NMR (CDCl3, 50 MHz) d: 143.7; 138.0; 129.4; 127.4;
49.6; 31.8; 21.6; 20.7; 13.7.
1.3.5. cis-N-p-Toluenesulfonyl-2-pentyl-3-methylaziri-
dine 14.44 Purification: eluent petroleum ether/ethyl acetate
10:1; yield: 45%. 1H NMR (CDCl3, 200 MHz) d: 7.79–7.83
(2H, m); 7.30–7.34 (2H, m); 2.91 (1H, dq, J¼5.9, 7.2 Hz);
2.61 (1H, dt, J¼5.4, 7.5 Hz); 2.43 (3H, s); 1.36–1.44 (2H,
m); 1.17–1.22 (9H, m); 0.77–0.90 (3H, m).
1.2. Materials
Starting materials were commercially available unless
otherwise stated. All commercial reagents were used
without further purification except diisopropyl amine,
which was distilled over calcium hydride. Tetrahydrofuran
was obtained anhydrous by distillation over sodium wire
after the characteristic blue color of in situ generated sodium
diphenylketyl52 was found to persist. Pentane was stored
over lithium aluminum hydride. Methylene chloride was
1.3.6. trans-N-p-Toluenesulfonyl-2-pentyl-3-methylaziri-
dine 15.44 Purification: eluent petroleum ether/ethyl acetate
9:1; yield: 34%. 1H NMR (CDCl3, 200 MHz) d: 7.81–7.85
(2H, m); 7.29–7.33 (2H, m); 2.68 (2H, m); 2.43 (3H, s);
1.40–1.65 (5H, m); 1.05–1.35 (6H, m); 0.90 (3H, t, J¼
6.4 Hz). 13C NMR (CDCl3, 50 MHz) d: 143.7; 138.1; 129.4;
127.3; 49.7; 45.8; 31.2; 30.4; 26.8; 22.4; 21.5; 14.7; 13.8.
˚
dried over calcium chloride and stored over 4 A molecular
sieves. Petroleum ether, unless specified, was the 40–708C
boiling fraction.
1.3.7. N-p-Toluenesulfonyl-1,2,3,4-tetrahydronaphta-
lene-1,2-amine 25.54 Purification: recrystallization from
hexane; yield: 34%. H NMR (CDCl3, 200 MHz) d: 7.84–
1.3. General procedure for the synthesis of N-p-toluene-
sulfonylaziridines (6a, 11–15, 25)
1
7.80 (2H, m); 7.03–7.33 (6H, m); 3.82 (1H, d, J¼7.4 Hz);
3.56 (1H, bd, J¼6.6 Hz); 2.73 (1H, dd, J¼6.6, 13.0 Hz);
2.48–2.59 (1H, m); 2.42 (3H, s); 2.21–2.31 (1H, m); 1.61–
1.76 (1H, m). 13C NMR (CDCl3, 50 MHz) d: 144.2; 136.6;
130.0; 129.7; 129.4; 128.7; 128.6; 128.4; 126.3; 127.6; 42.1;
41.7; 24.7; 21.6; 20.0. MS (m/z, %): 147 (12); 146 (11); 145
(27); 118 (21); 117 (31); 116 (21); 115 (28), 114 (14); 105
(34); 104 (27); 103 (100); 91 (27); 84 (61); 76 (47); 65 (16);
62 (29), 50 (38); 49 (30); 43 (38), 40 (46).
In a round bottomed flask, a solution of chloramine-T
(0.704 g, 2.5 mmol) and iodine (0.254 g, 1.0 mmol) in
acetonitrile (10 mL) was prepared. After the complete
dissolution of iodine, 5.0 mmol of the suitable alkenes (11:
cyclopentene, 0.340 g; 6a: cyclohexene, 0.410 g; 12:
cyclooctene, 0.551 g; 13: trans-4-octene, 0.561 g; 14:
cis-2-octene, 0.561 g; 15: trans-2-octene, 0.561 g; 25:
dihydronaphtalene, 0.651 g) were added. The mixture was
stirred at room temperature for 24 h before quenching with
H2O (50 mL), and extracted with CH2Cl2 (3£50 mL); the
organic layers were combined and washed with H2O
(2£50 mL) and brine (2£50 mL), and then dried. Evapo-
ration of the solvent gave the aziridines 6a, 11–15, 25,
which were purified by flash chromatography.
1.4. Preparation of other N-activated aziridines
1.4.1. 2-Azidocyclohexanol.55 A solution of cyclohexene
oxide (9.815 g, 100 mmol) and sodium azide (16.260 g,
250 mmol) in 110 mL of a 1:1 mixture of acetone/water was
heated at reflux for 17 h. The reaction was then cooled to
room temperature, and acetone was removed under reduced
pressure; the residual aqueous layer was washed with
1.3.1. N-p-Toluenesulfonyl-6-azabicyclo[3.1.0]hexane
11.43 Purification: eluent petroleum ether/ethyl acetate 4:1;
yield: 68%. 1H NMR (CDCl3, 200 MHz) d: 7.78–7.82 (2H,

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A. Mordini et al. / Tetrahedron 58 (2002) 7153–7163
methyl tert-butyl ether (3£50 mL) and CH2Cl2 (3£50 mL);
the organic layers were combined, washed with H2O
(3£50 mL) and dried. Evaporation of the solvent gave
14.10 g of 2-azidocyclohexanol (100 mmol, yield 100%) as
a pale yellow oil. The product was used in the following
reaction without any further purification. 1H NMR (CDCl3,
200 MHz) d: 3.30–3.41 (1H, m); 3.10–3.22 (1H, m); 2.58
(1H, bs); 1.94–2.08 (2H, m); 1.68–1.76 (2H, m); 1.22–1.35
(4H, m). 13C NMR (50 MHz) d: 73.5; 67.1; 32.9; 29.7; 24.2;
23.8.
(9H, s). 13C NMR (CDCl3, 50 MHz) d: 163.3; 80.5; 36.9;
28.0; 23.8; 19.9. MS (m/z, %): 141 (31); 126 (13); 124 (8);
97 (74); 96 (100); 82 (60); 81 (55); 69 (21); 68 (11); 57 (46);
41 (10).
1.4.5. N-Pivaloyl-7-azabicyclo[4.1.0]heptane 6d.57 Under
a nitrogen atmosphere, 8 (0.194 g, 2 mmol), triethylamine
(0.222 g, 2.2 mmol) and DMAP (few crystals) were
dissolved in 4 mL of anhydrous THF. The solution was
cooled to 08C, and then a solution of pivaloyl chloride
(0.241 g, 2 mmol) in 1 mL anhydrous THF was added. After
stirring for 15 min at 08C, the mixture was warmed to room
temperature, and the reaction was allowed to proceed
for 20 h. The solution was then quenched with H2O (5 mL),
the aqueous layer was extracted with Et2O (4£10 mL),
the combined organic layers were washed with brine
(2£20 mL), and dried. Evaporation of the solvent gave
crude 6d, which was purified by flash column chroma-
tography (6% ethyl acetate in petroleum ether; yield 40%;
1.4.2. 7-Azabicyclo[4.1.0]heptane 8.27,55 To a solution
of 2-azidocyclohexanol (14.100 g, 100 mmol) in 50 mL of
anhydrous THF, triphenylphosphine (26.230 g, 100 mmol),
dissolved in 30 mL of anhydrous THF, was added dropwise
over 30 min; the resulting mixture was heated at reflux and
the reaction was allowed to proceed for 17 h. The reaction
was then cooled to room temperature and the solvent was
removed by distillation at atmospheric pressure. Distillation
at reduced pressure (bp 55–578C/6.8 mm Hg) afforded
7.510 g of pure 8 (77 mmol, yield 77%) as a colorless oil.
1H NMR (CDCl3, 200 MHz) d: 2.14–2.17 (2H, m); 1.77–
1.84 (4H, m); 1.21–1.40 (4H, m); 0.60 (1H, bs). 13C NMR
(CDCl3, 50 MHz) d: 29.3; 24.5; 20.0. MS (m/z, %): 97 (2,
Mþ); 96 (13, Mþ21); 82 (49); 69 (49); 68 (100); 54 (11).
1
colorless oil). H NMR (CDCl3, 200 MHz) d: 2.62–2.64
(2H, m); 1.76–2.02 (4H, m); 1.27–1.46 (4H, m); 1.23 (9H,
s). 13C NMR (CDCl3, 50 MHz) d: 192.3; 41.2; 36.0; 28.1;
23.8; 20.0. MS (m/z, %): 181 (9, Mþ); 180 (12, Mþ21); 166
(63); 138 (19); 131 (33); 100 (11); 97 (19); 96 (100); 85
(10); 67 (51); 55 (33); 54 (32); 53 (29); 41 (74).
1.4.3. N-Benzenesulfonyl-7-azabicyclo[4.1.0]heptane
6b.56 To a solution of 8 (0.971 g, 10 mmol) in 50 mL of
anhydrous pyridine, few crystals of DMAP were added;
after cooling the solution to 08C, benzenesulphonyl chloride
(1.765 g, 10 mmol) was added under nitrogen. The reaction
was allowed to proceed for 2 h, then, after warming to room
temperature, 150 mL Et2O were added, the organic layer
was washed with a saturated solution of CuSO4 (until
complete disappearance of the blue color of the copper/
pyridine complex), and subsequently with H2O (2£50 mL),
and then dried. Evaporation of the solvent gave the desired
product 6b, which was purified by flash column chroma-
tography (petroleum ether/ethyl acetate 8:1; yield 40%; pale
1.4.6. 2-Trifluoroacetylaminocyclohexanol. Under
a
nitrogen atmosphere, 2-aminocyclohexanol hydrochloride
(1.213 g, 8 mmol), pyridine (2.513 g, 32 mmol) and DMAP
(few crystals) were dissolved in 50 mL of anhydrous
CH2Cl2. The solution was cooled to 2168C and then
trifluoroacetic anhydride was added (3.360 g, 16 mmol).
The mixture was warmed to room temperature and the
reaction was allowed to proceed for 1 h. The solvent was
subsequently removed in vacuo, and replaced with 60 mL
methanol; the resulting mixture was stirred for 2 h, then
methanol was evaporated and replaced with 60 mL ethyl
acetate. The organic phase was washed with a saturated
solution of NaHCO3 (2£60 mL) and the aqueous layer was
extracted with ethyl acetate (4£40 mL). The combined
organic layers were finally washed with brine (2£60 mL)
and dried. Evaporation of the solvent afforded 1.345 g of
pure 2-trifluoroacetylaminocyclohexanol (6.4 mmol, yield
80%) as a white solid, which was then used without further
1
yellowish oil). H NMR (CDCl3, 200 MHz) d: 7.92–7.97
(2H, m); 7.50–7.66 (3H, m); 3.00 (2H, m); 1.77–1.82 (4H,
m); 1.21–1.41 (4H, m). 13C NMR (CDCl3, 50 MHz) d:
138.8; 133.1; 128.9; 127.5; 40.0; 22.8; 19.4. MS (m/z, %):
141 (2); 96 (100); 77 (30); 69 (51); 55 (11); 51 (19).
1
purification. H NMR (CDCl3, 200 MHz) d: 6.53 (1H, m);
1.4.4. N-tert-Butoxycarbonyl-7-azabicyclo[4.1.0]heptane
6c.27 Under a nitrogen atmosphere, 8 (0.194 g, 2 mmol),
triethylamine (0.525 g, 5.2 mmol) and DMAP (few crystals)
were dissolved in 3 mL anhydrous CH2Cl2. The solution
was cooled to 08C and then di-tert-butyldicarbonate
(0.905 g, 5.2 mmol) was added; after stirring for 10 min at
08C, the mixture was warmed to room temperature and the
reaction was allowed to proceed for 2 h. The reaction was
then quenched with H2O (20 mL), and the resulting mixture
was diluted with a saturated solution of ammonium chloride
(20 mL). The aqueous phase was extracted with Et2O
(2£25 mL) and the combined organic layers were washed
with saturated solutions of KHSO4 (20 mL), Na2CO3
(20 mL) and NaCl (20 mL), and dried. Evaporation of the
solvent gave crude 6c, which was purified by flash column
chromatography (5% ethyl acetate in petroleum ether; yield
70%; yellow oil). 1H NMR (CDCl3, 200 MHz) d: 2.54–2.56
(2H, m); 1.70–1.95 (4H, m); 1.16–1.54 (4H, m); 1.44
3.64 (1H, m); 3.41 (1H, m); 2.06–2.12 (2H, m); 1.72–1.81
(3H, m); 1.16–1.39 (4H, m). 13C NMR (CDCl3, 50 MHz) d:
156.0; 116.0 (q, J¼278 Hz); 73.4; 56.4; 34.6; 30.9; 24.3;
24.1. MS (m/z, %): 193 (22); 114 (20); 98 (67); 97 (20); 86
(17); 81 (17); 80 (29); 79 (17); 70 (27); 69 (54); 68 (18); 58
(16) 57 (55); 56 (18); 55 (25); 54 (16); 44 (45); 43 (56); 42
(45); 41 (100); 40 (29).
1.4.7. 1-Methansulfonyloxy-2-trifluoroacetylaminocyclo-
hexane. 2-Trifluoroacetylamino-cyclohexanol (1.335 g,
6.3 mmol) was dissolved in 10 mL of anhydrous pyridine,
under nitrogen. The resulting solution was cooled to 08C
and methanesulfonyl chloride (0.802 g, 7 mmol) was added
dropwise. After stirring for 2 h, the reaction was warmed to
room temperature and 80 mL ethyl acetate were added. The
organic layer was washed with a saturated solution of
CuSO4 (until complete disappearance of the blue color of
the copper/pyridine complex), H2O (2£80 mL) and brine

A. Mordini et al. / Tetrahedron 58 (2002) 7153–7163
7159
(2£80 mL), and dried. Evaporation of the solvent afforded
1.552 g of pure 1-methansulfonyloxy-2-trifluoroacetyl-
aminocyclohexane (5.4 mmol, yield 85%) as a white solid,
which was then used without further purification. 1H NMR
(CDCl3, 200 MHz) d: 6.83 (1H, m); 4.56 (1H, dt, J¼4.6,
10.6 Hz); 3.92 (1H, m); 3.03 (3H, s); 2.11–2.30 (2H, m);
1.57–1.86 (2H, m); 1.27–1.38 (4H, m). MS (m/z, %): 210
(22); 194 (20); 193 (22); 166 (38); 165 (100); 152 (84); 126
(42); 124 (32); 97 (81); 96 (26); 81 (46); 80 (72); 79 (88); 69
(46); 41 (29).
yield: 30%; pale yellowish oil. 1H NMR (CDCl3,
200 MHz) d: 7.87–7.91 (2H, m); 7.51–7.58 (3H, m);
5.74–5.80 (1H, m); 5.30–5.35 (1H, m); 4.41–4.58 (1H, m);
3.82 (1H, bs); 1.25–1.94 (4H, m); 0.79–0.97 (2H, m). 13C
NMR (CDCl3, 50 MHz) d: 143.8; 132.5; 131.7; 129.1;
126.9; 49.1; 30.3; 24.5; 19.3. MS (m/z, %): 96 (28); 91 (17);
79 (19); 77 (100); 76 (48); 68 (25); 67 (25); 66 (17); 55 (16);
54 (17); 53 (23); 51 (55); 50 (58); 49 (21); 43 (16); 42 (22),
41 (86); 40 (69).
1.5.4. 1-N-p-Toluenesulfonylaminobicyclo[3.3.0]octane
17.28 Purification: eluent petroleum ether/ethyl acetate 4:1;
yield: 64%. 1H NMR (CDCl3, 200 MHz) d: 7.74–7.78 (2H,
m); 7.27–7.31 (2H, m); 4.47 (1H, m); 3.54 (1H, m); 2.41
(3H, s); 2.20–2.40 (2H, m); 0.90–1.90 (10H, m). 13C NMR
(CDCl3, 50 MHz) d: 143.1; 137.8; 129.5; 127.0; 57.0; 45.5;
41.2; 35.5; 30.6; 29.4; 28.1; 27.3; 21.5. MS (m/z, %): 155
(17); 124 (14); 109 (3); 92 (11); 91 (100); 89 (10); 77 (8); 65
(19); 55 (17); 41 (13).
1.4.8. N-Trifluroacetyl-7-azabicyclo[4.1.0]heptane 6e.
1-Methansulfonyloxy-2-trifluoroacetylamino-cyclohexane
(0.145 g, 0.5 mmol) was dissolved in 4.5 mL anhydrous
THF, under nitrogen. The resulting solution was cooled to
2788C, and then a solution of 1 M LiHMDS in THF
(0.5 mL, 0.5 mmol) was added dropwise. After 3 h, the
solvent was removed in vacuo and replaced with an equal
volume of anhydrous pentane; the solution was filtered over
a fritted-glass septum and the solvent evaporated, affording
1
25 mg of 6e (0.13 mmol, yield 26%) as a white solid. H
1.5.5. 5-N-p-Toluenesulfonylamino-3-octene 22. Purifi-
cation: eluent petroleum ether/ethyl acetate 8:1; yield: 48%.
1H NMR (CDCl3, 200 MHz) d: 7.69–7.73 (2H, m); 7.24–
7.28 (2H, m); 5.36 (1H, dt, J¼15.4, 6.2 Hz); 5.01 (1H, dd,
J¼15.4, 7.4 Hz); 4.28 (1H, m); 3.71 (1H, m); 2.41 (3H, s);
1.82 (2H, quint, J¼6.6 Hz); 1.22–1.43 (4H, m); 0.84 (3H, t,
J¼7.2 Hz); 0.79 (3H, t, J¼7.4 Hz). 13C NMR (CDCl3,
50 MHz) d: 142.9; 138.3; 134.1; 129.3; 128.3; 127.2; 55.9;
38.2; 25.0; 21.4; 18.6; 13.6; 13.1. MS (m/z, %): 281 (6, Mþ);
239 (16); 238 (91); 207 (20); 155 (55); 92 (13); 91 (100); 83
(12); 80 (11); 79 (12); 73 (16); 65 (25); 55 (13). Anal. calcd
for C15H23NO2S: C, 64.02; H, 8.24; N, 4.98. Found: C,
63.91; H, 8.16; N, 4.90.
NMR (CDCl3, 200 MHz) d: 2.96 (2H, bs); 1.62–2.10 (4H,
m); 1.25–1.50 (4H, m). MS (m/z, %): 193 (3, Mþ); 96 (100);
82 (4); 81 (20); 69 (51); 42 (13); 41 (17).
1.5. General procedure for the isomerization of N-sul-
fonylaziridines using LIDAKOR in pentane at room
temperature
A solution of BuLi in hexane (0.66 mL of a 1.5 M solution,
1.0 mmol) was mixed with pentane (1.5 mL), diisopropyl-
amine (101 mg, 1.0 mmol) and potassium tert-butoxide
(112 mg, 1.0 mmol), at 08C under nitrogen; the mixture was
stirred at 08C for 15 min, after which the aziridine
(0.5 mmol) was added and allowed to react for 15–18 h at
room temperature. The reaction was then quenched with
H2O (10 mL) and extracted with Et2O (3£10 mL). The
organic layers were combined and washed with H2O
(2£15 mL) and brine (2£15 mL), and then dried. Evapor-
ation of the solvent gave the isomerization products, which
were purified by flash chromatography.
1.5.6. 3-N-p-Toluenesulfonylamino-1-octene 23.60 Purifi-
cation: eluent petroleum ether/ethyl acetate/triethylamine
1
87:11.5:1.5; yield: 20%. H NMR (CDCl3, 200 MHz) d:
7.74–7.78 (2H, m); 7.29–7.33 (2H, m); 5.54 (1H, ddd,
J¼6.4, 10.0, 16.8 Hz); 4.98 (1H, d, J¼16.8 Hz); 4.95 (1H, d,
J¼10.0 Hz); 4.57 (1H, m); 3.85 (1H, q, J¼6.4 Hz); 2.43
(3H, s); 0.82–1.36 (11H, m). MS (m/z, %): 210 (67); 155
(60); 126 (6); 91 (100); 79 (11); 77 (11); 73 (21); 68 (11); 67
(12); 65 (34); 55 (12); 54 (11).
1.5.1. 3-N-p-Toluenesulfonylamino-cyclopentene 16.58
Purification: eluent petroleum ether/ethyl acetate 4:1;
yield: 42%. 1H NMR (CDCl3, 200 MHz) d: 7.75–7.79
(2H, m); 7.29–7.33 (2H, m); 5.87 (1H, m); 5.43 (1H, m);
4.40 (2H, m); 2.42 (3H, s); 2.00–2.40 (2H, m); 1.20–1.80
(2H, m). 13C NMR (CDCl3, 50 MHz) d: 143.2; 138.1; 135.0;
130.4; 129.6; 127.0; 59.8; 31.6; 30.8; 21.5. MS (m/z, %):
149 (100); 104 (12); 76 (24); 65 (10); 57 (11); 55 (10).
1.5.7. 2-N-p-Toluenesulfonylamino-3-octene 24. Purifi-
cation: eluent petroleum ether/ethyl acetate/triethylamine
1
87:11.5:1.5; yield: 40%. H NMR (CDCl3, 200 MHz) d:
7.71–7.75 (2H, m); 7.25–7.29 (2H, m); 5.39 (1H, dt, J¼
15.5, 6.4 Hz); 5.14 (1H, dd, J¼15.5, 6.6 Hz); 4.55 (1H,
m); 3.73 (1H, quint, J¼6.6 Hz); 2.43 (3H, s); 1.83 (2H,
m); 0.82–1.36 (10H, m). MS (m/z, %): 267 (11); 198 (5);
155 (32); 126 (22); 111 (11); 110 (25); 92 (12); 91 (100);
82 (15); 81 (12); 79 (11); 73 (24); 70 (11); 69 (10); 68
(29); 67 (11); 65 (24); 55 (25). Anal. calcd for C15H23NO2S:
C, 64.02; H, 8.24; N, 4.98. Found: C, 64.11; H, 8.29; N,
5.08.
1.5.2. 3-N-p-Toluenesulfonylaminocyclohexene 7a.28
Purification: eluent petroleum ether/ethyl acetate 9:2;
yield: 46%. 1H NMR (CDCl3, 200 MHz) d: 7.74–7.78
(2H, m); 7.26–7.30 (2H, m); 5.75 (1H, m); 5.30 (1H, m); 4.60
(1H, m); 3.78 (1H, bs); 2.41 (3H, s); 1.10–1.90 (6H, m). 13C
NMR (CDCl3, 50 MHz) d: 143.1; 138.3; 131.4; 129.6; 127.0;
126.9; 49.0; 30.2; 24.5; 21.5; 19.3. MS (m/z, %): 159 (4); 155
(21); 96 (47); 91 (100); 82 (2); 81 (11); 80 (14); 79 (25); 77
(11); 69 (11); 68 (29); 67 (14); 65 (44).
1.6. General procedure for the isomerization of N-tosyl-
aziridines using LICKOR in THF at 2508C (2208C)
Hexane was stripped off from a solution of BuLi (0.66 mL
of a 1.5 M solution, 1.0 mmol) and precooled THF (2.0 mL)
was added at 2788C under nitrogen, followed by potassium
1.5.3. 3-N-Benzenesulfonylaminocyclohexene 7b.59
Purification: eluent petroleum ether/ethyl acetate 3:1;

7160
A. Mordini et al. / Tetrahedron 58 (2002) 7153–7163
tert-butoxide (112 mg, 1.0 mmol). The mixture was stirred
at 2788C for 30 min, after which the aziridine (0.5 mmol)
was added and allowed to react for 15–18 h at 2508C
(2208C). The reaction was then quenched with H2O
(10 mL), and extracted with Et2O (3£10 mL). The organic
layers were combined and washed with H2O (2£15 mL) and
brine (2£15 mL), and then dried; evaporation of the solvent
gave the isomerization products which were purified by
flash chromatography.
(3£30 mL) and the organic phases were added to a solution
obtained by dissolving 5 g of NaCl and 30 g of NaOH in
90 mL of H2O. After 1 h of vigorous stirring, the two phases
were separated, the water phase was extracted with Et2O
(3£50 mL) and the organic layers were combined and dried.
Evaporation of the solvent gave 1.83 g of the desired
1
product (83%). H NMR (CDCl3, 200 MHz) d: 7.45–7.10
(5H, m); 3.89 (1H, bd, J¼12.6 Hz); 3.61 (1H, bd, J¼
12.6 Hz); 3.22 (1H, td, J¼5.6, 2.2 Hz); 3.04–2.98 (1H, m);
2.96–2.90 (2H, m); 2.45 (1H, bs).
1.6.1. 3-N-p-Toluenesulfonylaminocyclooctene 18.61
Purification: eluent petroleum ether/ethyl acetate 4:1;
1.8.2. (2R,3R )-1-Methoxymethoxy-2,3-epoxy-4-phenyl-
butane. To a solution of (2R,3R )-4-phenyl-2,3-epoxy-1-
butanol (1.82 g, 11 mmol) in CH2Cl2 (25 mL) at 08C,
N,N-diisopropylethylamine (3.80 mL, 22 mmol) and
chloromethyl methyl ether (1.25 mL, 16.6 mmol) were
added under nitrogen. The mixture was stirred at room
temperature for 14 h and then washed with an aqueous
solution of 10% HCl (25 mL), sat. NaHCO3 (3£30 mL) and
brine (3£30 mL). The organic layer was dried over
anhydrous Na2SO4. The solvent was evaporated and the
crude oxiranyl ether obtained (2.04 g, 89%) as a yellow oil.
1H NMR (CDCl3, 200 MHz) d: 7.40–7.10 (5H, m); 4.62
(2H, s); 3.73 (1H, dd, J¼11.8, 3.6 Hz); 3.54 (1H, dd,
J¼11.8, 5.6 Hz); 3.34 (3H, s); 3.10 (1H, td, J¼5.6, 2.2 Hz);
3.04–2.96 (1H, m); 2.92–2.86 (2H, m).
1
yield: 33% (at 2508C). H NMR (CDCl3, 200 MHz) d:
7.71–7.75 (2H, m); 7.26–7.30 (2H, m); 5.56 (1H, qapp, J¼
9.0 Hz); 5.11 (1H, tapp, J¼9.2 Hz); 4.39 (1H, m); 4.20 (1H,
m); 2.42 (1H, s); 2.05 (2H, m); 1.00–1.80 (8H, m). 13C
NMR (CDCl3, 50 MHz) d: 143.1; 133.5; 131.0; 130.2;
129.4; 127.1; 51.5; 37.1; 29.7; 29.0; 26.4; 24.2; 21.5. MS
(m/z, %): 155 (13); 124 (98); 109 (2); 92 (13); 91 (100); 89
(11); 77 (10); 68 (11); 67 (13); 65 (24); 55 (36); 53 (12); 41
(13).
1.6.2. 1-N-p-Toluenesulfonylaminobicyclo[3.3.0]octane
17.28 Purification: eluent petroleum ether/ethyl acetate 4:1;
yield: 48% (at 2208C).
1.7. General procedure for the isomerization of N-tosyl-
aziridines using LIDAKOR in THF at 2508C
1.8.3. (2S,3S)-1-Methoxymethoxy-2-hydroxy-3-azido-4-
phenylbutane, (2S,3R )-1-methoxymethoxy-2-azido-3-
Hexane was stripped off from a solution of BuLi (0.66 mL
of a 1.5 M solution, 1.0 mmol) and precooled THF (2.0 mL)
was added at 2788C under nitrogen, followed by diiso-
propylamine (101 mg, 1.0 mmol) and potassium tert-
butoxide (112 mg, 1.0 mmol). The mixture was stirred at
2788C for 30 min, after which the aziridine (0.5 mmol) was
added and allowed to react for 15–18 h at 2508C. The
reaction was then quenched with H2O (10 mL) and
extracted with Et2O (3£10 mL). The organic layers were
combined and washed with H2O (2£15 mL) and brine
(2£15 mL), and then dried; evaporation of the solvent gave
the isomerization products which were purified by flash
chromatography.
hydroxy-4-phenylbutane.
To
(2R,3R)-1-methoxy-
methoxy-2,3-epoxy-4-phenylbutane (1.94 g, 9.3 mmol) in
2-methoxyethanol/water, 8:1 (63 mL), NaN3 (3.63 g,
55.8 mmol) and NH4Cl (1.00 g, 18.6 mmol) were added
under N2. The mixture was stirred at 808C for 6 h before
H2O (20 mL) and Et2O (40 mL) were added. The water
phase was extracted with Et2O (3£50 mL) and the organic
layers were collected, washed with H2O (3 60 mL) and
dried. Evaporation of the solvent gave 1.88 g (80%) as a
mixture of regioisomeric azido alcohols as a brown oil. MS
(m/z, %): 177 (2, Mþ2OH–N3–CH3); 161 (2, Mþ2OH–
N3–OCH3); 146 (3); 133 (5); 105 (17); 91 (100, C7Hþ7 ); 73
(42); 65 (32).
1.7.1. 3-N-p-Toluenesulfonylaminocyclohexene 7a.28
Purification: eluent petroleum ether/ethyl acetate 9:2;
yield: 64%.
1.8.4. (2R,3S)-3-Benzyl-2-methoxymethoxymethylaziri-
dine. A mixture of (2S,3S)-1-methoxymethoxy-2-hydroxy-
3-azido-4-phenylbutane and (2S,3R)-1-methoxymethoxy-
2-azido-3-hydroxy-4-phenylbutane (1.74 g, 6.9 mmol),
anhydrous toluene (30 mL) and triphenylphosphine
(2.18 g, 8.3 mmol) was refluxed under N2 for 24 h. After
removing the solvent under reduced pressure, the
residue was dissolved in CH2Cl2 and filtered over Celitew
to remove OPPh3. The filtrated was evaporated giving
1.48 g (quantitative) of crude aziridine. 1H NMR
(CDCl3, 200 MHz) d: 7.50–7.10 (5H, m); 4.60 (2H, s);
3.68 (1H, dd, J¼12.0, 5.3 Hz); 3.47 (1H, dd, J¼12.0,
4.0 Hz); 3.40 (1H, m); 3.33 (3H, s); 2.80 (2H, m); 2.20–2.00
(2H, m).
1.8. Preparation of heterosubstituted aziridinyl ethers
1.8.1. (2R,3R )-4-Phenyl-2,3-epoxy-1-butanol. Molecular
˚
sieves 4 A (1.26 g), CH2Cl2 (50 mL), (D)-(2)-diethyl
tartrate (0.42 mL, 2.43 mmol) and Ti(OiPr)4 (0.60 mL,
2.01 mmol) were mixed under nitrogen and cooled to
t
2238C. BuOOH (5.9 mL of a 5.5 M solution in decane,
˚
dried over molecular sieves 4 A, 32.28 mmol) was then
slowly added and the mixture maintained at 2238C
for 30 min before (E)-4-phenyl-but-2-en-1-ol (1.99 g,
13.45 mmol) in CH2Cl2 (7 mL) was slowly added. After
48 h a solution obtained by dissolving 33 g of FeSO4·7H2O
and 11 g citric acid in 100 mL of H2O and cooled at 08C was
added and the mixture warmed up to room temperature.
The two phases, which were formed after stirring, were
separated; the water phase was extracted with Et2O
1.8.5. (2R,3S )-3-Benzyl-2-methoxymethoxymethyl-1-p-
toluenesulfonylaziridine 26.50 To a solution of (2R,3S )-
2-[(methoxymethoxy)methyl]-3-benzylaziridine (1.55 g,
7.48 mmol) in CH2Cl2 (40 mL) at 08C, 4-(dimethylamino)-
pyridine (170 mg, 0.7 mmol), triethylamine (2.1 mL,

A. Mordini et al. / Tetrahedron 58 (2002) 7153–7163
7161
15 mmol) and p-toluenesulfonyl chloride (2.16 g,
11.3 mmol) were added under nitrogen. The reaction
mixture was stirred at 258C for 12 h before H2O (30 mL)
was added. The water phase was then extracted with CH2Cl2
(3£40 mL) and the organic layers were collected and
washed with H2O (3£50 mL), brine (3£40 mL) and dried.
The solvent was evaporated under reduced pressure and the
crude was then purified by flash chromatography (petroleum
ether/ethyl acetate, 4:1) affording 1.24 g (46%, 94% ee
determined via Mosher ester) of 26 as a yellow oil. 1H NMR
(CDCl3, 200 MHz) d: 7.74 (2H, d, J¼8.2 Hz); 7.15–7.00
(7H, m), 4.52 (2H, s); 3.79 (2H, m); 3.25 (3H, s); 3.10–3.00
(4H, m); 2.43 (3H, s). 13C NMR (CDCl3, 50 MHz) d: 143.8;
137.3; 137.2; 129.3; 128.5; 128.4; 127.4; 126.5; 96.3; 65.6;
55.2; 47.6; 47.2; 35.6; 21.5. MS (m/z, %): 286 (8, Mþ2
CH2OMOM); 270 (6, Mþ2C7Hþ7 ); 210 (11); 194 (3); 174
(6); 155 (8, Ts); 146 (24); 139 (44); 138 (17); 129 (13); 117
(9); 104 (14); 91 (100, C7Hþ7 ); 77 (30); 65 (49); 54 (56).
Anal. calcd for C19H23NO4S: C, 63.14; H, 6.41; N, 3.88.
Found: C, 63.21; H, 6.29; N, 3.68.
1.8.8. (2R,3R )-1-Methoxymethoxy-2-hydroxy-3-azido-
octane, (2R,3S)-1-methoxymethoxy-3-hydroxy-2-azido-
octane. To the oxiranyl ether (1.65 g, 8.7 mmol) in
2-methoxyethanol/water, 8:1 (55 mL), NaN3 (3.45 g,
53 mmol) and NH4Cl (0.96 g, 18 mmol) were added under
N2. The mixture was stirred at 808C for 12 h then H2O
(30 mL) and Et2O (100 mL) were added. The two phases
were separated; the water phase was extracted with Et2O
(3£30 mL), and the organic layers were washed with H2O
(3£50 mL), dried and evaporated. The resulting azido
alcohol was purified by flash chromatography (petroleum
ether/AcOEt, 2:1) affording 1.21 g (60%) of a mixture of
1
regioisomers. H NMR (CDCl3, 200 MHz) d: 4.65 (2H, s);
3.7 (4H,m); 3.37 (3H, s); 2.82 (1H, bs); 1.5 (2H, m); 1.29
(6H, m); 0.88 (3H, t, J¼6.6 Hz). MS (m/z, %): 105 (33,
CH3OCH2OCH2CHvOHþ); 98 (11); 87 (8); 75 (13); 73
(100); 71 (15); 57 (22); 56 (17); 55 (25).
1.8.9. (2R,3R )-1-Methoxymethoxy-2-methansulfonyl-
oxy-3-azidooctane, (2R,3S )-1-methoxymethoxy-3-meth-
ansulfonyloxy-2-azidooctane. The mixture of (2R,3R )-1-
methoxymethoxy-2-hydroxy-3-azidooctane and (2R,3S )-1-
methoxymethoxy-3-hydroxy-2-azidooctane (1.62 g, 7.0 mmol)
and anhydrous pyridine (16 mL) were mixed under N2 and
cooled at 08C. Methanesulfonyl chloride (985 mg,
8.6 mmol) was added and the mixture stirred at room
temperature for 24 h before Et2O was added (16 mL). The
mixture was then washed with sat. CuSO4 (until complete
disappearance of the blue color of the copper/pyridine
complex), H2O (3£20 mL), dried and evaporate, giving
˚
1.8.6. (2S,3S)-2,3-Epoxyoctanol. Molecular sieves 4 A
(0.6 g), CH2Cl2 (70 mL), (L)-(þ)-diethyl tartrate (266 mg,
1.3 mmol) and Ti(OiPr)4 (412 mg, 1.44 mmol) were mixed
under N2 and cooled to 2238C. tBuOOH (7.4 mL of a 5.5 M
˚
solution in decane, dried over molecular sieves 4 A,
40.6 mmol) was then slowly added and the mixture
maintained at 2208C for 30 min before (E)-2-octenol
(2.56 g, 20 mmol) was added. After 18 h, a solution
obtained by dissolving 3.55 g of FeSO4 and 1.35 g citric
acid in 10 mL of H2O and cooled at 08C was added and the
mixture warmed up to room temperature. The two
phases, which were formed after stirring, were separated;
the water phase was extracted with Et2O (3£10 mL) and the
organic phases were added to a solution obtained by
dissolving 0.5 g of NaCl and 3.0 g of NaOH in 9.0 mL of
H2O. After 45 min of vigorous stirring the two phases were
separated, the water phase was extracted with Et2O
(3£10 mL) and the organic layers were combined and
dried. Evaporation of the solvent gave 2.33 g of the desired
1
1.73 g (80%) as a mixture of mesylated azido alcohols. H
NMR (CDCl3, 200 MHz) d: 4.69 (1H, dt, J¼5.6, 4.6 Hz);
4.65 (2H, s); 3.79 (1H, d, J¼1.2 Hz); 3.76 (1H, m); 3.70
(1H, m); 3.37 (3H, s); 3.10 (3H, s); 1.6–1.1 (8H, m); 0.89
(3H, m).
1.8.10. (2S,3R )-2-Methoxymethoxymethyl-3-pentylaziri-
dine. The mixture of (2R,3R )-1-methoxymethoxy-2-
methansulfonyloxy-3-azidooctane and (2R,3S)-1-methoxy-
methoxy-3-methansulfonyloxy-2-azidooctane (0.36 g, 1.18
mmol) in THF (5 mL) was stirred under nitrogen at 08C.
LiAlH4 (3.5 mmol) was added and the reaction mixture was
allowed to warm to room temperature. After 2 h it was
warmed up to 508C for 12 h. The reaction was then
quenched with H2O and aqueous NH4Cl, after cooling to
08C. The mixture was filtered over Celitew and the organic
layer was dried. The evaporation of the solvent gave 0.209 g
(94%) of the desired aziridine. 1H NMR (CDCl3, 200 MHz)
d: 4.62 (2H, s); 3.63 (1H, dd, J¼10.8, 4.6 Hz); 3.43 (1H, dd,
J¼10.8, 6 Hz); 3.35–3.34 (1H,m); 3.33 (3H, s); 1.85 (1H,
m); 1.78 (1H, m); 1.40 (2H, m); 1.25 (6H,m); 0.89 (3H, m).
MS (m/z, %): 188 (2, Mþþ1); 156 (2, Mþ2CH3O); 142 (4,
Mþ2CH3OCH2); 126 (52, Mþ2CH3OCH2O); 112 (53,
Mþ2CH2OMOM); 82 (34); 69 (100); 56 (86).
1
product (81%). H NMR (CDCl3, 200 MHz) d: 3.90 (1H,
dd, J¼12.8, 2.6 Hz); 3.60 (1H, dd, J¼12.8, 4.4 Hz); 2.94
(2H, m); 2.20 (1H, bs); 1.54 (2H, m); 1.30 (6H, m); 0.90
(3H, t, J¼6.6 Hz). 13C NMR (CDCl3, 50 MHz) d: 61.7;
58.6; 56.0; 31.5; 31.5; 25.6; 25.6; 13.9. MS (m/z, %): 101 (4,
Mþ2C3H7); 83 (95); 71 (10); 69 (12); 61 (11); 57 (67); 56
(44); 55 (100).
1.8.7. (2S,3S )-1-Methoxymethoxy-2,3-epoxyoctane. To a
solution of (2S,3S)-2,3-epoxyoctanol (927 mg, 6.4 mmol)
in CH2Cl2 (40 mL) at 08C, N,N-diisopropylethylamine
(2.2 mL, 12.8 mmol) and chloromethyl methyl ether
(0.73 mL, 9.6 mmol) were added under nitrogen. The
mixture was stirred at room temperature for 12 h and then
washed with 10% HCl (30 mL), sat. NaHCO3 (3£25 mL)
and brine (3£25 mL). The organic layer was dried over
anhydrous Na2SO4. Evaporation of the solvent gave
(2S,3S)-1-methoxymethoxy-2,3-epoxyoctane (1.04 g, 87%).
1H NMR (CDCl3, 200 MHz) d: 4.64 (2H, s); 3.73 (1H, dd,
J¼11.4, 5.4 Hz); 3.53 (1H, dd, J¼11.4, 3.4 Hz); 3.37 (3H,
s); 2.92 (1H, ddd, J¼5.4, 3.4, 2.4 Hz); 2.83 (1H, ddd, J¼6.1,
5.4, 2.4 Hz); 1.5 (2H, m); 1.3 (6H, m); 0.87 (3H, t, J¼
7.2 Hz).
1.8.11. (2S,3R )-2-Methoxymethoxymethyl-3-pentyl-1-p-
toluenesulfonylaziridine 27.50 To a solution of (2S,3R )-2-
methoxymethoxymethyl-3-pentylaziridine (0.807 g, 4.31
mmol) in anhydrous pyridine (40 mL) at 08C, p-toluene-
sulfonyl chloride (0.820 g, 4.3 mmol) was added under N2.
The reaction mixture was stirred at 08C for 20 min before
Et2O (20 mL) was added. The mixture was then washed
with sat. CuSO4 solution (until complete disappearance of

7162
A. Mordini et al. / Tetrahedron 58 (2002) 7153–7163
the blue color of the copper/pyridine complex), H2O
(3£30 mL), dried and the solvent removed under vacuum.
The crude product was purified by flash chromatography
(petroleum ether/ethyl acetate, 6:1) giving 0.965 g (65%,
84% ee determined via Mosher ester) of pure 27. 1H NMR
(CDCl3, 200 MHz) d: 7.84 (2H, m); 7.30 (2H, m); 4.54 (2H,
s); 3.76 (2H, m); 3.27 (3H, s); 2.92 (1H, dt, J¼5.8, 4.4 Hz);
2.74 (1H, dt, J¼6.6, 4.4 Hz); 2.42 (3H, s); 1.75 (2H, m);
1.25 (6H, m); 0.84 (3H, m,). 13C NMR (CDCl3, 50 MHz) d:
146.0; 143.1; 129.9; 127.3; 108.0; 95.6; 56.5; 53.9; 36.2;
31.0; 25.1; 23.0; 21.8; 15.6; 14.0. MS (m/z, %); 210 (37);
186 (28, Mþ2Ts); 155 (35, Ts); 140 (8); 91 (100); 69 (16);
65 (39); 55 (18); 54 (31). Anal. calcd for C17H27NO4S: C,
59.80; H, 7.97; N, 4.10. Found: C, 59.76; H, 8.02; N, 4.18.
(petroleum ether/ethyl acetate, 2:1) giving 34 mg (56%) of
1
aldehyde 32. H NMR (CDCl3, 200 MHz) d: 9.64 (1H, s);
7.74 (2H, m); 7.29 (2H, m); 4.82 (1H, d, J¼8.4 Hz); 3.57
(1H, m); 2.62 (2H, m); 2.42 (3H, s); 1.42 (2H, m); 1.30–
1.00 (6H, m); 0.79 (3H, t, J¼6.0 Hz). 13C NMR (CDCl3,
50 MHz) d: 205.0; 143.5; 138.0; 130.0; 127.0; 49.5; 38.0;
35.0; 31.0; 25.0; 23.0; 21.0; 14.0. MS (m/z, %): 254
(7, Mþ2CH2COH); 226 (20); 207 (3); 172 (24); 155
(82); 142 (10); 91 (100); 65 (6). Anal. calcd for
C15H23NO3S: C, 60.58; H, 7.79; N, 4.71. Found: C, 60.72;
H, 7.90; N, 4.63.
1.10.2. (3R )-3-N-p-Toluenesulfonyl-octanoic acid 33.50,62
To a solution of aldehyde 32 (49 mg, 0.16 mmol) in
MeCN/H2O, 3:1 (0.8 mL) at 08C, 0.94 mL of a solution
obtained dissolving H5IO6 (5.7 g) and CrO3 (11.5 mg) in
MeCN: H2O, 3:1 (5.7 mL) was slowly added. The reaction
mixture was stirred for 6 h before sat. Na2HPO4 (4 mL) and
toluene (4 mL) were added. The organic phase was washed
with a solution of brine: H2O, 1:1 (5 mL), sat. NaHSO3
(3£5 mL) and brine (3£5 mL). After evaporation of the
solvent, the crude was purified by flash chromatography
(petroleum ether/ethyl acetate, 1:1) affording 26 mg (52%)
of pure acid 33. 1H NMR (CDCl3, 200 MHz) d: 7.77 (2H, d,
J¼8.4 Hz); 7.29 (2H, d, J¼8.4 Hz); 5.40–4.80 (1H, bs);
3.49 (1H, m); 2.48 (2H, d, J¼5.2 Hz); 2.42 (3H, s); 1.45
(2H, m); 1.40–1.00 (6H, m); 0.81 (3H, m). 13C NMR
(CDCl3, 50 MHz) d: 173.7; 141.1; 135.5; 127.8; 124.5;
46.5; 38.2; 32.1; 28.5; 22.3; 20.0; 19.7; 11.8.
1.9. Isomerization of heterosubstituted aziridines
1.9.1. (3E )-(2R )-1-Methoxymethoxymethyl-4-phenyl-2-
(N-p-toluenesulfonyl)ammino-3-butene 28.50 The general
procedure with LIDAKOR in pentane was used on aziridine
26, obtaining a crude product which was then purified by
flash chromatography (petroleum ether/ethyl acetate, 3:2)
giving 76 mg (70%, 91% ee determined via Mosher ester) of
28. 1H NMR (CDCl3, 200 MHz) d: 7.73 (2H, d, J¼8.6 Hz);
7.30–7.10 (7H, m); 6.39 (1H, d, J¼15.8 Hz); 5.86 (1H, dd,
J¼15.8, 7.4 Hz); 5.21 (1H, d, J¼7.0 Hz); 4.56 (2H, s); 4.12
(1H, m); 3.58 (2H, d, J¼4.8 Hz); 3.32 (3H, s); 2.33 (3H, s).
13C NMR (CDCl3, 50 MHz) d: 143.3; 138.0; 136.1; 132.7;
129.5; 128.4; 127.9; 127.3; 126.4; 125.8; 96.7; 70.5; 55.7;
55.5; 21.4. MS (m/z, %): 300 (1, Mþ2OMOM); 286 (64,
Mþ2CH2OMOM); 206 (2); 226 (1); 184 (3); 176 (4); 155
(33); 145 (6); 130 (33); 115 (25); 103 (7); 91 (100); 77 (1);
65 (23). Anal. calcd for C19H23NO4S: C, 63.14; H, 6.41; N,
3.88. Found: C, 63.26; H, 6.49; N, 3.69.
References
1. Atkinson, R. S. Tetrahedron 1999, 55, 1519–1559.
2. McCoull, W.; Davis, F. A. Synthesis 2000, 1347–1365.
3. Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997,
8, 1693–1715.
1.9.2. (1E )-(3R )-1-Methoxymethoxy-3-N-p-toluenesulfo-
nylamino-1-octene 29.50 The general procedure was used
on aziridine 27, obtaining 1.21 g (78%) of a crude product
which was then purified by flash chromatography (petro-
leum ether/ethyl acetate, 4:1) giving 864 mg (56%, 81% ee
determined via Mosher ester) of 29. 1H NMR (CDCl3,
200 MHz) d: 7.73 (2H, m); 7.28 (2H, m); 6.09 (1H, dd,
J¼12.5, 0.8 Hz); 4.68 (1H, dd, J¼12.5, 4.7 Hz); 4.62 (2H,
s); 4.58–4.42 (1H, m); 3.80–3.46 (1H, m); 3.29 (3H, s);
2.41 (3H, s); 1.6–1.0 (8H, m); 0.88 (3H, m). 13C NMR
(CDCl3, 50 MHz) d: 145.9; 143.0; 138.4; 129.1; 127.2;
107.8; 95.5; 55.7; 53.2; 36.5; 31.2; 25.1; 22.4; 21.4; 13.9.
MS (m/z, %): 254 (10); 210 (91); 187 (71, Mþ291); 171 (5,
NH2Ts); 155 (83, Ts); 140 (19); 91 (100); 84 (53); 69 (15);
68 (24); 65 (15); 57 (13). Anal. calcd for C17H27NO4S: C,
59.80; H, 7.97; N, 4.10. Found: C, 59.72; H, 7.92; N, 4.13.
4. Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. Comprehensive
Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon: Oxford,
1996; Vol. 1A, p 1.
5. Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599–619.
6. Satoh, T. Chem. Rev. 1996, 96, 3303.
7. Crandall, J. K.; Apparu, M. Org. React. 1983, 29, 345.
8. Thummel, R. P.; Rickborn, B. J. Am. Chem. Soc. 1970, 92.
9. Morgan, K. M.; Gronert, S. J. Org. Chem. 2000, 65, 1461.
10. Mordini, A.; BenRayana, E.; Margot, C.; Schlosser, M.
Tetrahedron 1990, 46, 2401.
11. Schlosser, M. J. Organomet. Chem. 1967, 8, 9.
12. Mordini, A. Comprehensive Organometallic Chemistry II;
Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds. (McKillop,
A. volume Ed.) Pergamon: Oxford, 1995; Vol. 11, p 93.
13. Margot, C.; Schlosser, M. Tetrahedron Lett. 1985, 26, 1035.
14. Asami, M. J. Synth. Org. Chem. Jpn 1996, 54, 188.
15. Cox, P. J.; Simpkins, N. S. Tetrahedron: Asymmetry 1991, 2,
1.
1.10. Elaboration of amino vinyl ethers
1.10.1. (3R )-3-N-p-Toluenesulfonylammino-1-octanal
32.50 To a solution of 29 (68 mg, 0.2 mmol) in CH2Cl2
(2 mL) at 2788C, Bu4NI (74 mg, 0.2 mmol) and Me3SiCl
(0.17 mL, 0.2 mmol) were added under nitrogen. The
reaction mixture was stirred at 2208C for 24 h, before sat.
NaHCO3 (1 mL) and THF (3 mL) were added. The mixture
was stirred for 10 min and then extracted with Et2O
(3£5 mL), washed with brine (3£5 mL), dried and evapo-
rated. The crude was purified by flash chromatography
16. Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996,
52, 14361.
17. O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439.
18. Milne, D.; Murphy, P. J. J. Chem. Soc., Chem. Commun. 1993,
884.
19. Hodgson, D. M.; Witherington, J.; Moloney, B. A. J. Chem.
Soc., Perkin Trans. 1 1994, 3373.

A. Mordini et al. / Tetrahedron 58 (2002) 7153–7163
7163
20. Bhuniya, D.; DattaGupta, A.; Singh, V. K. J. Org. Chem.
1996, 61, 6108.
21. Asami, M. Chem. Lett. 1984, 829.
42. Simkhovic, L.; Gross, Z. Tetrahedron Lett. 2001, 42, 8089.
43. Jeoung, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless,
K. B. J. Am. Chem. Soc. 1998, 120, 6844.
¨
22. Sodergren, M. J.; Andersson, P. G. J. Am. Chem. Soc. 1998,
120, 10760.
44. Ando, T.; Kano, D.; Minakata, S.; Ryu, I.; Komatsu, M.
Tetrahedron 1998, 54, 13485.
23. Asami, M.; Suga, T.; Honda, K.; Inoue, S. Tetrahedron Lett.
1997, 38, 6425.
24. Asami, M.; Inoue, S. Tetrahedron Lett. 1995, 51, 11725.
¨
25. Bertilsson, S. K.; Sodergren, M. J.; Andersson, P. G. J. Org.
Chem. 2002, 67, 1567.
45. Kano, D.; Minakata, S.; Komatsu, M. J. Chem. Soc., Perkin
Trans. 1 2001, 3186.
46. Tanner, D.; Somfai, P. Tetrahedron 1988, 44, 619.
47. Boc is not always inert towards nucleophile as recently
underlined in the following review article: Agami, C.; Couty,
F. Tetrahedron 2002, 58, 2701.
¨
26. Sodergren, M. J.; Bertilsson, S. K.; Andersson, P. G. J. Am.
Chem. Soc. 2000, 122, 6610.
48. Apparu, M.; Barrelle, M. Tetrahedron 1978, 34, 1541.
49. It has been reported that a-elimination occurs with dimeric
LDA while b-elimination is favoured with monomeric
reagent: Ramirez, A.; Collum, D. B. J. Am. Chem. Soc.
1999, 121, 11114.
27. da Zhang, Z.; Scheffold, R. Helv. Chim. Acta 1993, 76, 2602.
28. Mu¨ller, P.; Nury, P. Helv. Chim. Acta 2001, 84, 662.
29. O’Brien, P.; Pilgram, C. D. Tetrahedron Lett. 1999, 40, 8427.
30. Mordini, A.; Pecchi, S.; Capozzi, G.; Capperucci, A.;
Degl’Innocenti, A.; Reginato, G.; Ricci, A. J. Org. Chem.
1994, 59, 4784.
50. These results have been already published in a preliminary
communication: Mordini, A.; Sbaragli, L.; Valacchi, M.;
Russo, F.; Reginato, G. Chem. Commun. 2002, 778.
51. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
52. Schlenk, W.; Bergmann, E. Liebigs Ann. Chem. 1928, 464, 22.
53. Chanda, B. M.; Vyas, R.; Bedekar, A. V. J. Org. Chem. 2001,
66, 30.
31. Mordini, A.; Bindi, S.; Pecchi, S.; Degl’Innocenti, A.;
Reginato, G.; Serci, A. J. Org. Chem. 1996, 61, 4374–4378.
32. Mordini, A.; Bindi, S.; Pecchi, S.; Capperucci, A.;
Degl’Innocenti, A.; Reginato, G. J. Org. Chem. 1996, 61,
4466–4468.
33. Mordini, A.; Valacchi, M.; Pecchi, S.; Degl’Innocenti, A.;
Reginato, G. Tetrahedron Lett. 1996, 37, 5209.
54. Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc.
1994, 116, 2742.
34. Mordini, A.; Valacchi, M.; Nardi, C.; Bindi, S.; Poli, G.;
Reginato, G. J. Org. Chem. 1997, 62, 8557–8559.
35. Mordini, A.; Bindi, S.; Capperucci, A.; Nistri, D.; Reginato,
G.; Valacchi, M. J. Org. Chem. 2001, 66, 3201.
36. Thurner, A.; Faigl, F.; Mordini, A.; Bigi, A.; Reginato, G.;
Toke, L. Tetrahedron 1998, 54, 11597.
55. Christoffers, J.; Schulze, Y.; Pickardt, J. Tetrahedron 2001, 57,
1765.
56. Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982, 104,
2444.
57. Tisue, G. T.; Linke, S.; Lwowski, W. J. Am. Chem. Soc. 1967,
89, 6303.
37. Thurner, A.; Faigl, F.; Toke, L.; Mordini, A.; Valacchi, M.;
Reginato, G.; Czira, G. Tetrahedron 2001, 57, 8173.
38. Ando, T.; Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron
Lett. 1998, 39, 309.
58. Kim, D. Y.; Kim, H. S.; Choi, Y. J.; Mang, J. Y.; Lee, K. Synth.
Commun. 2001, 31, 2463.
59. Barashenkov, G. G.; Derkach, N. Y. J. Org. Chem. USSR
1986, 1069.
39. Albone, D. P.; Aujla, P. S.; Taylor, P. C. J. Org. Chem. 1998,
63, 9569.
60. Yadav, J. S.; Bandyopadhyay, A.; Reddy, B. V. S. Synlett
2001, 1608.
40. Antunes, A. M. M.; Marto, S. J. L.; Branco, P. S.; Prabhakar,
S.; Lobo, A. M. Chem. Commun. 2001, 405.
61. Mahy, J. P.; Bedi, G.; Battioni, P.; Mansuy, D. Tetrahedron
Lett. 1988, 29, 1927.
41. Mansuy, D.; Mahy, J. P.; Dureault, A.; Bedi, G.; Battioni, P.
J. Chem. Soc., Chem. Commun. 1984, 1161.
62. Jefford, C. W.; McNulty, J.; Lu, Z. H.; Wang, J. B. Helv. Chim.
Acta 1996, 79, 1203.