Iminoiodane mediated aziridination of α-allylglycine: Access to a novel rigid arginine derivative and to the natural amino acid enduracididine

Article abstract of DOI:10.1016/j.tet.2004.05.034

The synthesis of fully protected aminodihydrohistidines in optically pure form is described starting from allylglycine derivatives. These compounds represent novel conformationally constrained analogues of arginine, one of them being, in addition, a protected form of the marine natural product, enduracididine. The key step of the strategy is a one-pot copper-catalyzed aziridination of t-butyl (S)-N-(9-phenyl-9H-fluoren-9-yl)allylglycinate ((S)-16) with 2-trimethylsilylethanesulfonamide in the presence of iodosylbenzene.

Full text of DOI:10.1016/j.tet.2004.05.034

Tetrahedron 60 (2004) 5889–5897
Iminoiodane mediated aziridination of a-allylglycine:
access to a novel rigid arginine derivative and to the natural
amino acid enduracididine
a
Laurent Saniere, Loıc Leman, Jean-Jacques Bourguignon, Philippe Dauban
a
b
a
,
*
`
¨
and Robert H. Dodda
,
*
aInstitut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
´
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081, CNRS, Faculte de Pharmacie, 74 route du Rhin,
b
67400 Illkirch, France
Received 29 March 2004; revised 30 April 2004; accepted 14 May 2004
Available online 9 June 2004
Abstract—The synthesis of fully protected aminodihydrohistidines in optically pure form is described starting from allylglycine derivatives.
These compounds represent novel conformationally constrained analogues of arginine, one of them being, in addition, a protected form of the
marine natural product, enduracididine. The key step of the strategy is a one-pot copper-catalyzed aziridination of t-butyl (S)-N-(9-phenyl-
9H-fluoren-9-yl)allylglycinate ((S)-16) with 2-trimethylsilylethanesulfonamide in the presence of iodosylbenzene.
q 2004 Published by Elsevier Ltd.
The conformational restriction of flexible bioactive
molecules is a well known technique for increasing their
intrinsic activity or their selectivity for a particular receptor
subtype or enzyme isoform.1,2 Such rigid ligands can also
lead to greater lipophilicity and/or increased stability toward
metabolic enzymes, both factors contributing to improved
bioavailability of a given active substance. A case in point is
arginine (1), the endogenous substrate of NO synthase, of
which a number of conformationally restricted analogues
have been prepared over the past years with these
considerations in mind. Such rigid analogues have generally
taken three forms. In the first, the essential guanidine
function (or an isosteric equivalent) is incorporated in a
chain-terminating heterocycle. These include, for
instance, the Nd–Nv ethylene bridged analogue 23 and the
2-aminopyrimidine derivative 34 (Fig. 1).
Figure 1. Arginine and rigid derivatives.
In the second class of compounds, the 3-carbon tether is
thrombin inhibitor.7 Alternatively, a compound in which the
locked into a more rigid conformation either by introduction
terminal amino function is bonded to the methylene
of a double bond (i.e. 4)5 or by incorporation as a ring (i.e.,
backbone would force arginine to adopt a highly folded
the guanidinophenylalanine derivative 5).5,6 Another
conformation as opposed to the extended conformations
approach to rigid arginine analogues consists in linking
exhibited by compounds 2–6. Interestingly, such a
one of the nitrogen atoms of the guanidine functionality to
compound, the aminodihydrohistidine 7 (enduracididine),
one of the methylene groups. One such molecule is the
has been isolated from natural sources. Thus, 7 was
piperidine derivative 6, designed in this case to be a specific
identified in 1968 as a component of a peptide antibiotic
enduracidin,8a itself isolated from Streptomyces
Keywords: Arginine mimetic; Allylglycine; Aziridine; Aziridination;
fungicidicus.8b,c Several years later, enduracididine was
Iminoiodane.
also shown to be a component of the antibiotic minosamino-
mycin, isolated from a plant source, Lonchocarpus
*
Corresponding authors. Tel.: þ33-1-69-82-45-94; fax: þ33-1-69-07-72-
47; e-mail address: robert.dodd@icsn.cnrs-gif.fr
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.05.034

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L. Saniere et al. / Tetrahedron 60 (2004) 5889–5897
5890
sericeus.9 More recently, this amino acid has been identified
in the cytotoxic fraction of extracts of a marine ascidian,
Leptoclinides dubius.10 While it has been reported that the
structure of enduracididine was established by X-ray
crystallography,8a the only published preparation of this
compound was by way of a Bamberger cleavage of methyl
histidinate which yielded a 1:1 mixture of enduracididine
and its (4S) isomer.11
and subsequent application to the synthesis of protected
enduracididine 7.
The optically pure starting allylglycine substrates were
prepared by enzymatic resolution of racemic ethyl N-Boc-
allylglycinate 12 using a-chymotrypsin (Scheme 2).21 This
procedure afforded (S)-N-Boc-allylglycine 13 with 98%
optical purity and the unreacted isomer (R)-12 (ee¼94%).
The choice of protecting groups for the carboxylic acid and
amine functionalities of 13 was made based on the
following considerations. Firstly, since in the retrosynthetic
scheme we planned to generate a diamino intermediate 9,
protection of the carboxylic acid with a bulky t-butyl group
was deemed necessary to prevent lactamization during this
step. Secondly, while the N-Boc group may be considered
both sufficiently bulky and electron-withdrawing to mini-
mize the aforementioned possibility of copper sequestration
during the aziridination step, preliminary experiments
showed that the yield of aziridination products was very
low.22 The phenylfluorenyl group was considered a suitable
choice in this case, combining both a large steric hindrance
around the nitrogen atom with the possibility of selective
removal. Thus, the Boc protecting group of compound 13
was removed by treatment with trifluoroacetic acid in
dichloromethane (Scheme 2). The resulting free amino acid
(S)-14 was then transiently esterified by reaction with
trimethylsilyl chloride. Treatment of the product in situ with
9-bromo-9-phenylfluorene in the presence of lead (II)
nitrate23 then provided after methanolic work-up the
N-phenylfluorenyl (NPhF)-protected derivative (S)-15.
Finally, reaction of the latter with t-butyl 2,2,2-trichloro-
acetimidate24 yielded the desired fully protected (S)-
allylglycine 16. Similar treatment of ethyl (R)-N-Boc-
allylglycine 12 then led to (R)-16. HPLC analysis of (S)-16
and (R)-16 using a chiral column (C-18 Waters Symmetry)
showed that no epimerization had occurred during these
deprotection/protection steps.
Thus, with the double incentive of preparing a new
conformationally restricted arginine analogue and a natural
product, we set about to develop a synthesis of endura-
cididine (in fact, a protected form of this molecule suitable
for insertion in small biologically active peptide derivatives
to furnish novel peptidomimetics). A retrosynthetic analysis
of this compound (Scheme 1) suggested that it could be
obtained from the guanidino derivative 8, which in turn
could be constructed from the diamine 9 for which purpose a
variety of reagents are available.12 The diamino compound
9 could then be prepared by amine (or equivalent) promoted
opening of the aziridine 10 itself formed by diastereo-
selective aziridination of L-allylglycine 11. The key step in
this pathway then was the preparation of aziridine 10 from a
suitably protected allylglycine derivative.
The (R) isomer of 16 was first used to optimize the copper-
catalyzed aziridination of the double bond. We have
previously demonstrated that the aziridination of a wide
range of olefins can be achieved using a convenient one-pot
procedure.25 Thus, by simply mixing 1 equiv. of (R)-16,
1.2 equiv. of PhIvO and of SesNH2 in the presence of
25 mol% of Cu(CH3CN)4PF6 in acetonitrile at room
Scheme 1. Retrosynthetic analysis.
Interestingly, while both the epoxide13 and cyclopropane14
analogues of aziridine 10 have been described, derivatives
of 10 itself have not.15 A particularly attractive way of
achieving this would be by application of the iminoiodane-
mediated copper (I or II)-catalyzed aziridination of
olefins.16,17 In addition, the iminoiodane derived from
trimethylsilylethanesulfonamide (SesNH2) seemed particu-
larly suited to this purpose as the Ses protecting group can
be removed under mild conditions (F2) avoiding possible
racemization of the amino acid.18 On the other hand, the
application of this copper-catalyzed aziridination procedure
to a nitrogen-containing olefinic substrate presented a
certain challenge since it could be anticipated that the
copper I or II salt would be sequestered by this nitrogen
atom, thereby inhibiting the desired reaction. Indeed, while
the copper-catalyzed iminoiodane-mediated aziridination
procedure has been successfully used recently as a key step
in the total synthesis of a number of natural products starting
from non-nitrogenous substrates,17 only very few
examples19,20 have been reported of this reaction being
applied to nitrogen-containing starting materials. In this
paper then, we report the results of our study in this regard
Scheme 2. Preparation of allylglycine derivatives. (a) a-chymotrypsin.21
(b) TFA, CH2Cl2, rt, 2 h. (c) HCl, EtOH. (d) Propylene oxide, EtOH, reflux,
7 h. (e) 6 N HCl, reflux, 18 h. (f) TMSCl, CH2Cl2, reflux, 2 h. (g) PhFBr,
Pb(NO3)2, CH2Cl2, rt, 84 h. (h) Cl3CC(vNH)Ot-Bu, cyclohexane, CH2Cl2,
rt, 72 h.

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5891
Table 1. ‘One-pot’ copper-catalyzed aziridination of allylglycine derivative (R)-16
Entry
Cu(CH3CN)4PF6
25 mol%
25 mol%
25 mol%
25 mol%
Solvent
Temperature
% Yielda
Diastereomeric ratio (R,R): (R,S)
1
2
3
4
5
6
7
8
CH3CN
C6H6
rt
rt
rt
32 (67)
26 (45)
24 (44)
30 (74)
25 (53)
28 (60)
23
65:35
67:33
70:30
63:37
67:33
66:34
70:30
75:25
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
5 8C
45 8C
rt
rt
220 8C
25 mol%
50 mol%
25 mol%þ35 mol% 18
25 mol%þ35 mol% 18
16
a
Yields in parentheses based on consumed substrate.
temperature, the desired N-Ses aziridine 17 was obtained in
32% overall yield (67% yield based on recovered starting
material) (Table 1, entry 1). The aziridination was
moderately diastereoselective providing a 65:35 ratio (as
determined by 1H NMR) of the (2R,4R) and (2R,4S)
isomers, respectively, which could not be separated at this
stage (see below for the determination of the absolute
configurations).
by protection of the resulting amine with a phenylfluorenyl
group),23b the yield of the corresponding aziridine (R)-23
was again quite low (26%) and, in addition, no diastereo-
selectivity was observed. These results, combined with our
previous observations,18,27 strongly suggest that the bulky
amine and carboxylic acid blocking groups of allylglycine
16 are not the source of the low yields of aziridinated
product. The latter is more likely attributable to the
previously described poor reactivity of terminal mono-
substituted olefins under these conditions. The combined
presence of both sterically demanding substituents does,
however, appear to be necessary to ensure some diastereo-
selectivity in the aziridination step.
Several attempts were made to improve the yield and/or the
diastereoselectivity of the aziridination but all proved
somewhat unsatisfactory. Thus (Table 1), while use of
benzene or dichloromethane as the reaction solvent gave
moderately higher diastereoselectivities (34 and 40%,
respectively), this was at the detriment of yields (26 and
24%, respectively) (entries 2, 3). No substantial changes in
yields and diastereoselectivities were observed when the
reaction was run at colder (5 8C) or warmer (45 8C)
temperatures (entries 4, 5). Unexpectedly, doubling the
quantity of copper catalyst led to a slightly decreased
aziridine yield (entry 6).
Since, despite many attempts, neither the yield nor the
diastereoselectivity of the aziridination of (R)-allylglycine
derivative 16 could be further improved, the best reaction
conditions were now applied to (S)-16 having the same C-2
configuration as arginine and enduracididine. As expected
then, ‘one-pot’ aziridination of (S)-16 with SesNH2
provided an inseparable 7:3 mixture of aziridines 17 in
28% yield (65% based on consumed starting material)
(Scheme 4). Attribution of the C-4 configuration of each
isomer was made possible after intramolecular aziridine
ring opening by the secondary amine of 17, the resulting
cyclized products being more amenable to NMR analysis.
Thus, when the diastereomeric mixture of aziridines 17 was
heated at 110 8C for 70 h in DMF, two major compounds
were obtained. Separation of the compounds by column
chromatography afforded the cis 4-aminoproline (S,S)-24 in
46% yield28 and the diastereomeric trans-4-aminoproline
Evans has shown that high stereoselectivities can be
obtained when the iminoiodane-mediated aziridination
reaction of simple olefins (styrene, cinnamates) is conducted
in the presence of chiral bis(oxazoline) catalysts.26 When
35 mol% of such a ligand (the t-butyl derivative 18) was
added to the aziridination reaction medium of (R)-16, some
improvement in diastereoselectivity was observed both at
room temperature (40% de, entry 7) and at 220 8C (50% de,
entry 8) but again, at the expense of overall product yield
(23 and 16%, respectively).
In order to verify whether the presence of a nitrogen atom in
the olefinic substrate was responsible for the relatively low
aziridination yields, the same aziridination procedure was
applied to t-butyl 4-pentenoate 20 (prepared by DCC/
DMAP promoted esterification of carboxylic acid 19 by
t-butanol) (Scheme 3). The yield of aziridine 21 (25%) was
in fact no better than that starting from the analogous amine-
containing substrate (R)-16, indicating that the nitrogen
atom is most probably not interfering with the reaction.
Moreover, when the bulky t-butyl ester of allylglycine 16
was replaced by a smaller ethyl ester as in (R)-22 (prepared
by selective removal of the N-Boc group of (R)-12 followed
Scheme 3. Aziridination of test substrates. (a) t-BuOH, DCC, DMAP,
CH2Cl2, rt, 20 h. (b) SesNH2 PhlvO, 25 mol% Cu(CH3CN)4PF6, CH3CN,
rt, 16 h. (c) HClg, CH2Cl2, rt, 5 h. (d) PhFBr, K3PO4, CH3NO2, rt, 72 h.

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5892
Scheme 4. Determination of the stereochemistry. (a) Conditions for step b
in Scheme 3. (b) DMF, 110 8C, 70 h.
derivative (S,R)-24 in 17% yield. The configuration of the
Ses-amino group of the major compound (S,S)-24 was
1
clearly established by H NMR NOESY and NOEDIFF
experiments. Thus, while no direct correlation was observed
between H-2 and H-4, strong NOE effects between H-2 and
H-3 on one hand and H-3 and H-4 on the other hand were
evident, indicating a cis relationship between H-2 and H-4.
No such correlation could be observed between H-3 and H-4
in the minor product, though H-2 and H-3 were still strongly
correlated, thereby corroborating the H-2/H-4 trans
relationship in (S,R)-24. Based on these results, it may be
deduced that the major diastereomer formed by aziridina-
tion of (S)-16 is the (2S,4S) isomer and that of (R)-16 the
(2R,4R) isomer.
Scheme 5. End of the synthesis. (a) NaN3, BF3·OEt2, DMF, 65 8C, 80 h.
(b) PPh3, THF, H2O, reflux, 20 h. (c) MeSC(vNCbz)NHCbz, HgCl2,
DMF, Et3N, rt, 84 h. (d) CsF, DMF, 90 8C, 24 h.
aziridination procedure to an a-allylglycine derivative.
This subsequently permitted the preparation of novel rigid
analogues of arginine (i.e. 27) starting from the stereo-
isomeric aziridinated products 17. Interestingly, the
(2S,4R)-isomer of 27 is a protected form of a marine natural
product, enduracididine 7. The present methodology there-
fore represents a versatile approach for the preparation of
this compound, its isomers and its analogues.31
In order to prepare the required diamino intermediate of
type 9, opening of the aziridine ring of compound 17 (a
mixture of the (S,S) and (S,R) isomers) by azide anion was
then investigated (Scheme 5). Careful control of the reaction
conditions was required in order to minimize the afore-
mentioned intramolecular aziridine ring opening (heating
with NaN3 in DMF at 65 8C for 80 h in the presence of
1
boron trifluoride etherate). The H NMR spectrum of the
1. Experimental
1.1. General
crude reaction mixture showed that two major ring-opened
products 25, separated and purified by a combination of
column chromatography on silica gel and HPLC, had been
formed in a ratio identical to that of the diastereomeric
components of starting material 17 (7:3). The major
compound could thus be assigned the (2S,4S) configuration
and the minor compound the (2S,4R) configuration.
Melting points were measured in capillary tubes on a Bu¨chi
B-540 apparatus and are uncorrected. IR spectra of samples
were obtained either as KBr pellets or as films with a Nicolet
205 FT-IR or Fourier Perkin–Elmer 1600 FT-IR spec-
1
trometer. H NMR and 13C NMR were determined on a
The synthesis of the target rigid arginine derivatives was
completed as shown in Scheme 5. Thus, reduction of the
azide function of compound (S,S)-25 with triphenyl-
phosphine in the presence of water afforded the intermediate
amine29 which was reacted directly with S-methyl N,N0-
bis(benzyloxycarbonyl)isothiourea30 to give the protected
guanidine derivative (S,S)-26 in 80% yield. Treatment of
this compound with cesium fluoride in DMF at 90 8C for
24 h then provided in one step the dihydroaminoimidazole
derivative (S,S)-27, HPLC of which showed a diastereo-
meric purity of 99%. Identical treatment of (S,R)-25
provided compound (S,R)-27 (de of 98%). The latter is a
protected form of enduracididine 7.
Bruker AC 200 (200 MHz), AC 250 (250 MHz) or Aspect
1
3000 (300 MHz) instrument. H and 13C NMR chemical
shifts are given as d values with reference to Me4Si as
internal standard. Electron impact and chemical ionization
mass spectra were recorded on an AEI MS-50 and AEI
MS-9 spectrometer, respectively. High-resolution mass
spectra were obtained using a Kratos MS-80 spectrometer.
Optical rotations were determined with a JASCO P-1010
polarimeter. Thin-layer chromatography was performed on
silica gel 60 plates with a fluorescent indicator. The plates
were visualized with UV light (254 nm) and with a 3.5%
solution of phosphomolybdic acid in ethanol. All column
chromatography was conducted on silica gel 60 (230–240
mesh) at medium pressure (200 mbar). All solvents were
˚
In summary, we have described herein the first application
of the one-pot copper-catalyzed iminoiodane-mediated
distilled and stored over 4 A molecular sieves before use.
All reagents were purchased from the Aldrich Chemical Co.

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L. Saniere et al. / Tetrahedron 60 (2004) 5889–5897
5893
and were used without further purification. Elemental
analyses were performed at the ICSN, CNRS, Gif-sur-
Yvette.
5.24 (m, 2H), 5.42–5.58 (m, 1H), 7.18–7.70 (m, 13H); 13C
NMR (75 MHz, CDCl3) d 37.5, 54.9, 72.7, 120.5, 120.6,
124.9, 125.6, 125.9, 127.9, 128.2, 128.6, 128.9, 129.3,
129.4, 140.3, 141.3, 143.0, 146.6, 148.3, 174.7. HRESMS
m/z 378.1466 (MþNa)þ (C24H21NO2þNa requires
378.1470).
1.1.1. (S)-N-(t-Butyloxycarbonyl)allylglycine (13) and
ethyl (R)-N-(t-butyloxycarbonyl)allylglycinate ((R)-12).
These compounds were obtained by selective enzymatic
saponification of the (S) enantiomer of racemic ethyl N-(t-
butyloxycarbonyl)allylglycinate ((R,S)-12) with a-chymo-
trypsin following the procedure of Schricker et al.21 The
optical purity (ee) of each compound was determined by
HPLC on a reverse phase C-18 Waters Symmetry column
(4.6£250 mm) after derivatization using o-phthaldialde-
hyde and N-acetylcysteine as described.32 Compound 13:
1.1.4. t-Butyl (S)-N-(9-phenyl-9H-fluoren-9-yl)allylglyci-
nate ((S)-16). To a solution of compound (S)-15 (150 mg,
0.42 mmol) in dichloromethane (1 mL) was added a
solution of t-butyl 2,2,2-trichloroacetimidate (184 mg,
0.84 mmol) in cyclohexane (0.85 mL). The reaction mixture
was stirred for 72 h at rt, filtered through Celite and
evaporated to dryness under vacuum. The residue was
dissolved in dichloromethane (1 mL), treated again with the
same quantity of reagent in cyclohexane and stirred for
another 60 h. The residue obtained after filtration and
evaporation was purified by chromatography on silica gel
(heptane–ethyl acetate 19:1), affording compound (S)-16 as
a pale yellow solid (172 mg, 87%): mp 54–55 8C; [a]D22
2173 (c 1.13, CHCl3); IR (film) 3312, 2977, 1724,
1
[a]2D2 þ13 (c 1.15, MeOH), ee¼98%; H NMR (200 MHz,
CDCl3) d 1.46 (s, 9H), 2.50–2.70 (m, 2H), 4.40–4.52 (m,
1H), 4.95–5.05 (m, 1H, exchangeable with D2O), 5.10–
5.33 (m, 2H), 5.62–5.78 (m, 1H). Compound (R)-12: [a]D22
210 (c 0.92, MeOH), ee¼94%; 1H NMR (200 MHz,
CDCl3) d 1.29 (t, 3H, J¼7.1 Hz), 1.48 (s, 9H), 2.50–2.60
(m, 2H), 4.27 (q, 2H, J¼7.1 Hz), 4.42–4.52 (m, 1H), 5.10–
5.28 (m, 3H, 1H, exchangeable with D2O), 5.60–5.88 (m,
1H).
1448 cm21
;
ESMS m/z 434 (MþNa)þ; 1H NMR
(250 MHz, CDCl3) d 1.22 (s, 9H), 2.21–2.32 (m, 2H),
2.71 (t, 1H, J¼5.8 Hz), 3.12 (br s, 1H), 5.02–5.10 (m, 2H),
5.68–5.89 (m, 1H), 7.20–7.50 (m, 11H), 7.68–7.80 (m,
2H); 13C NMR (75 MHz, CDCl3) d 28.1, 40.4, 56.0, 73.2,
80.7, 117.3, 119.9, 125.5, 126.3, 127.2, 127.9, 128.3, 134.7,
140.3, 141.0, 145.1, 149.5, 149.6, 174.6. Anal. calcd for
C28H29NO2: C, 81.72; H, 7.10; N, 3.40. Found: C, 81.99; H,
7.17; N, 3.13.
1.1.2. (S)-Allylglycine ((S)-14). To a solution of compound
13 (2.7 g, 12.7 mmol) in dichloromethane (12 mL) held at
0 8C was slowly added trifluoroacetic acid (9.7 mL,
127 mmol). After completion of the addition, the reaction
mixture was stirred for 2 h at rt and then evaporated to
dryness under vacuum. The residue was dissolved in ethanol
(20 mL), 4 N HCl (3 mL) was added and the solution was
once again evaporated to dryness, leaving (S)-14 hydro-
chloride as a white powder (1.9 g, 98%): mp 206–208 8C.
1.1.5. t-Butyl (R)-N-(9-phenyl-9H-fluoren-9-yl)allylglyci-
nate ((R)-16). A suspension of compound (R)-12 (2.6 g,
10.7 mmol) in 6 N HCl was refluxed for 18 h. The reaction
mixture was cooled and evaporated to dryness under
vacuum by repeated co-evaporation with ethanol, affording
(R)-allylglycine as the hydrochloride salt ((R)-14 HCl) in
quantitative yield. Treatment of this compound in the same
manner as for (S)-14 HCl provided compound (R)-16
identical in all respects to (S)-16 except for the optical
rotation: [a]2D2 þ152 (c 5.0, CHCl3).
A sample of the latter (500 mg, 3.3 mmol) in absolute
ethanol (6.6 mL) was treated with propylene oxide
(1.15 mL, 16.5 mmol), the mixture was refluxed for 7 h,
cooled and the white precipitate of (S)-14 was collected by
filtration and washed with ether (324 mg, 85%). ESMS m/z
1
116 (MH)þ; H NMR (300 MHz, D2O) d 2.53–2.72 (m,
2H), 3.80 (dd, 1H, J¼5.1, 7.1 Hz), 5.23–5.32 (m, 2H),
5.69–5.85 (m, 1H); 13C NMR (75 MHz, D2O) d 35.5, 54.6,
121.1, 131.9, 174.7.
1.1.6. t-Butyl (2R,20RS)-2-N-[(9-phenyl-9H-fluoren-9-
yl)amino]-3-[N-(2-trimethylsilylethanesulfonyl)aziridin-
20-yl]propanoate ((R,RS)-17). To a suspension of activated
1.1.3. (S)-N-(9-Phenyl-9H-fluoren-9-yl)allylglycine ((S)-
15). To a suspension of (S)-allylglycine (S)-14 (300 mg,
2.61 mmol) in anhydrous dichloromethane (5 mL) was
added trimethylsilyl chloride (0.35 mL, 2.75 mmol). The
reaction mixture was stirred at rt for 10 min and then
refluxed for 2 h. The solution was cooled to rt, triethylamine
(0.73 mL, 5.22 mmol) was added followed after 15 min by
addition of lead (II) nitrate (0.59 g, 1.79 mmol) and of a
solution of 9-bromo-9-phenylfluorene (1.14 g, 3.56 mmol)
in dichloromethane (5 mL). The reaction mixture was
stirred for 84 h at rt. Methanol (2.5 mL) was added, and
after 2 h stirring, the mixture was filtered through Celite.
The filtrate was evaporated in vacuo and the residue was
chromatographed on silica gel (heptane–ethyl acetate 4:1
followed by 1:1) to afford compound (S)-15 as a colorless
solid (566 mg, 61%); mp 59–61 8C (lit.23a mp 63–64 8C);
[a]2D3 2 152 (c 1.01, CHCl3); IR (film) 2957, 2926, 1710,
˚
3 A molecular sieves (250 mg) in acetonitrile (1.3 mL) were
successively added compound (R)-16 (310 mg, 0.75 mmol)
and Cu(CH3CN)4PF6 (70 mg, 0.19 mmol). A mixture of 2-
trimethylsilylethanesulfonamide (178 mg, 0.98 mmol) and
iodosylbenzene (217 mg, 0.98 mmol) was then introduced
in five portions over a period of 1.5 h. The reaction mixture
was stirred overnight at room temperature then filtered
through a pad of Celite and concentrated under reduced
pressure. The residue was purified by flash chromatography
on silica gel (heptane–ethyl acetate 19:1 then 9:1) to afford
the N-(Ses)aziridines (R,RS)-17 (142 mg, 32%) as an
inseparable 7:3 mixture of diastereoisomers: IR (film)
1
1725, 1449, 1323 cm21; ESMS m/z 591 (MH)þ; H NMR
(300 MHz, CDCl3) d 0.05, 0.07 (2s, 9H), 1.05–1.15 (m,
2H), 1.20 (s, 9H), 1.25–1.45 (m, 1H), 1.8–2.05 (m, 2H),
2.4–2.7 (m, 2H), 2.75–3.1 (m, 3H), 7.2–7.45 (m, 11H),
7.65–7.75 (m, 2H); 13C NMR (75 MHz, CDCl3) d 21.9,
21.8, 9.4, 10.0, 28.0, 32.9, 33.6, 37.0, 37.5, 37.9, 48.7, 49.0,
1637 cm21
;
1H NMR (300 MHz, CDCl3) d 1.93–2.06
(m, 1H), 2.38–2.50 (m, 1H), 2.70 (t, 1H, J¼5.4 Hz), 5.10–

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L. Saniere et al. / Tetrahedron 60 (2004) 5889–5897
5894
54.6, 73.2, 81.5, 119.9, 120.1, 120.2, 125.6, 126.2, 126.4,
127.4, 128.0, 128.1, 128.3, 128.4, 128.5, 140.1, 141.2,
144.5, 144.7, 148.9, 149.2, 174.1, 174.2. Anal. calcd for
C33H42N2O4SSi: C, 67.07; H, 7.16; N, 4.74; S, 5.43. Found:
C, 67.27; H, 7.38; N, 4.56; S, 5.34.
affording ethyl (R)-allylglycinate hydrochloride (3.0 g,
100%): mp 89–91 8C; [a]2D6 þ1 (c 0.65, MeOH); IR (film)
1
3406, 2981, 1744, 1487 cm21; ESMS m/z 144 (MH)þ; H
NMR (250 MHz, CDCl3) d 1.30 (t, 3H, J¼7.1 Hz), 2.75–
2.95 (m, 2H), 4.05–4.35 (m, 3H), 5.26 (dd, 1H, J¼1.5,
10.1 Hz), 5.33 (dd, 1H, J¼1.5, 16.9 Hz), 5.75–5.95 (m,
1H), 8.70–8.90 (br s, 3H); 13C NMR (75 MHz, CDCl3) d
14.2, 34.6, 52.9, 62.6, 121.5, 130.3, 168.8.
1.1.7. t-Butyl (2S,20RS)-2-N-(9-phenyl-9H-fluoren-9-yl)-
amino-3-[N-(2-trimethylsilylethanesulfonyl)aziridin-20-
yl]propanoate ((S,RS)-17). Following the same procedure
as for the preparation of (2R,4RS)-17, compound (S)-16
A solution of this compound (500 mg, 2.78 mmol) in
nitromethane (5 mL) was then treated with potassium
phosphate (1.18 g, 5.54 mmol) and 9-bromo-9-phenyl-
fluorene (1.07 g, 3.3 mmol). The reaction mixture was
stirred at rt for 72 h, ethanol (2 mL) was added and after
5 min of stirring, the mixture was filtered through Celite.
The filter pad was washed with ethyl acetate, the filtrate and
washings were combined, evaporated to dryness under
vacuum and the residue was purified by column chroma-
tography on silica gel (heptane–ethyl acetate 19:1),
affording (R)-22 as a pasty solid (985 mg, 92%): [a]D22
þ195 (c 2.01, CHCl3); IR (film) 3314, 3062, 2979, 1729,
˚
(2.39 g, 5.8 mmol) in acetonitrile (25 mL) containing 3 A
molecular sieves (3.75 g) was treated with Cu(CH3CN)4PF6
(0.63 g, 1.68 mmol) and a mixture of SesNH2 (1.37 g,
7.6 mmol) and iodosylbenzene (1.7 g, 7.7 mmol) in five
portions. After the usual work-up, the crude product was
purified by chromatography on silica gel (ethyl acetate 1:19
then 1:9) affording compound (S,RS)-17 as a 7:3 mixture of
diastereomers (0.95 g, 28%) whose spectral characteristics
were identical to those of compound (R,RS)-17.
1.1.8. t-Butyl 4-pentenoate (20). A solution of 4-pentenoic
acid (1 g, 10 mmol), t-butanol (2.2 g, 40 mmol) and DMAP
(20 mg, 0.16 mmol) in dichloromethane (5 mL) was treated
at 0 8C with DCC (2.25 g, 11 mmol). The reaction mixture
was stirred for 15 min at 0 8C and then for 20 h at rt. The
precipitate was removed by filtration through Celite, the
filtrate was evaporated under vacuum, the residue was taken
up in dichloromethane (20 mL) and washed successively
with 0.1 M HCl (2£20 mL), saturated aqueous NaHCO3
(20 mL) and water (2£20 mL). The organic phase was dried
over MgSO4, the solvent was evaporated and the residue
was chromatographed on silica gel affording compound
2033 as a colorless oil (710 mg, 45%): IR (film) 2979, 2932,
1732, 1153 cm21; ESMS m/z 179 (MþNa)þ; 1H NMR
(250 MHz, CDCl3) d 1.45 (s, 9H), 2.31–2.35 (m, 4H),
4.96–5.10 (m, 2H), 5.73–5.92 (m, 1H); 13C NMR
(62.5 MHz, CDCl3) d 28.2, 29.2, 34.8, 80.3, 115.3, 137.1,
172.6.
1
1447 cm21; H NMR (300 MHz, CDCl3) d 0.96 (t, 3H,
J¼7.1 Hz), 2.10–2.29 (m, 2H), 2.65–2.73 (m, 1H), 2.93 (br
s, 1H), 3.58–3.70 (m, 1H), 3.70–3.82 (m, 1H), 4.97–5.01
(m, 1H), 5.01–5.05 (m, 1H), 5.61–5.76 (m, 1H), 7.13–7.72
(m, 13H); 13C NMR (75 MHz, CDCl3) d 14.1, 39.9,
55.7, 60.5, 73.1, 117.7, 119.9, 120.0, 125.5, 126.3, 127.3,
127.5, 127.9, 128.4, 134.4, 140.3, 141.1, 144.9, 147.0,
149.3, 175.7. HRESMS m/z 406.1793 (MþNa)þ
(C26H25NO2þNaþ requires 406.1783).
1.1.11. Ethyl (2R,20RS)-2-N-(9-phenyl-9H-fluoren-9-yl)-
amino-3-[N-(2-trimethylsilylethanesulfonyl)aziridin-20-
yl]propanoate ((R,RS)-23). Following the same procedure
as for the preparation of 17, compound (R)-22 (210 mg,
˚
0.55 mmol) in acetonitrile (2.2 mL) containing 3 A
molecular sieves (0.3 g) was treated with Cu(CH3CN)4PF6
(50 mg, 0.134 mmol) and a mixture of SesNH2 (131 mg,
0.72 mmol) and iodosylbenzene (156 mg, 0.71 mmol) in
five portions. After the usual work-up and chromatography
of the residue on silica gel (ethyl acetate–heptane 1:9 then
1:5), compound (R,RS)-23 was obtained as a 1:1 mixture of
diastereomers (80 mg, 26%): IR (film) 3310, 2953, 1730,
1.1.9. t-Butyl (R,S)-3-[N-(2-trimethylsilylethanesulfonyl)-
aziridin-20yl]propanoate (rac-21). Following the same
procedure as for the preparation of 17, compound 20
˚
(211 mg, 1.35 mmol) in acetonitrile (5.3 mL) containing 3 A
1
molecular sieves (0.7 g) was treated with Cu(CH3CN)4PF6
(126 mg, 0.34 mmol) and a mixture of SesNH2 (318 mg,
1.75 mmol) and iodosylbenzene (385 mg, 1.75 mmol) in five
portions. After the usual work-up, the crude product was
purified by chromatography on silica gel (ethyl acetate–
heptane 1:4), affording compound rac-21 as an orange oil
(115 mg, 25%): IR (film) 3297, 2954, 1729 cm21; 1H NMR
(250 MHz, CDCl3) d 0.07 (s, 9H), 1.10–1.17 (m, 2H), 1.44 (s,
9H), 1.62–1.75 (m, 1H), 1.90–2.02 (m, 1H), 2.13 (d, 1H,
J¼4.6 Hz), 2.38 (t, 2H, J¼7.0 Hz), 2.60 (d, 1H, J¼7.0 Hz),
2.73–2.82(m, 1H), 3.04–3.12(m, 2H);13C NMR (62.5 MHz,
CDCl3) d 21.9, 9.8, 26.9, 28.2, 32.6, 33.7, 38.0, 48.9, 80.9,
171.8. HRESMS m/z 358.1481 (MþNa)þ (C14H29NO4SSiþ
Naþ requires 358.1484).
1449 cm21; H NMR (300 MHz, CDCl3) d 0.05 (s, 9H),
0.07 (s, 9H), 0.80–1.13 (m, 10H), 1.30–1.60 (m, 2H),
1.77–2.00 (m, 2H), 1.87 (d, 1H, J¼4.4 Hz), 2.06 (d, 1H,
J¼4.4 Hz), 2.43 (d, 1H, J¼7.0 Hz), 2.63–3.2 (m, 9H),
3.63–3.87 (m, 4H), 7.08–7.47 (m, 22H), 7.66–7.76 (m,
4H); 13C NMR (75 MHz, CDCl3) d 21.9, 9.5, 10.0, 30.5,
32.7, 33.3, 37.0, 37.1, 37.2, 37.3, 48.8, 49.0, 54.2, 54.4,
61.1, 73.1, 120.0, 120.2, 125.5, 126.2, 126.4, 127.5, 127.6,
128.2, 128.4–128.7, 140.1, 141.4, 144.3, 144.5, 148.5,
148.6, 148.9, 149.0, 175.2, 175.3. HRESMS m/z 585.2200
(MþNa)þ (C31H38N2O4SSiþNaþ requires 585.2219).
1.1.12. t-Butyl (2S,4S)- and (2S,4R)-1-N-(9-phenyl-9H-
fluoren-9-yl)-4-N-(2-trimethylsilylethanesulfonyl)-
aminoproline ((S,S)-24 and (S,R)-24, respectively). A
solution of compound (S,RS)-17 (147 mg, 0.25 mmol) in
DMF (2 mL) was heated at 110 8C for 70 h. The solvent was
removed under vacuum and the residue was purified by
column chromatography on silica gel (heptane–ethyl
acetate 7:1) affording by order of elution compounds
1.1.10. Ethyl (R)-N-(9-phenyl-9H-fluoren-9-yl)allylglyci-
nate ((R)-22). HCl gas was bubbled through a solution of
compound (R)-12 (4.0 g, 16.4 mmol) in dichloromethane
(50 mL) for 75 min. The reaction mixture was stirred at rt
for 5 h and then evaporated to dryness under vacuum

`
L. Saniere et al. / Tetrahedron 60 (2004) 5889–5897
5895
(S,S)-24 and (S,R)-24. Compound (S,S)-24: (67 mg, 46%):
[a]2D5 þ102 (c 0.91, CHCl3); IR (film) 3274, 2956, 1720,
Minor diastereomer (S,R)-25: IR (film) 3283, 2954, 2929,
2103, 1724, 1449 cm21; 1H NMR (300 MHz, CDCl3) d 0.09
(s, 9H), 1.00–1.10 (m, 2H), 1.25 (s, 9H), 1.50–1.64 (m,
2H), 2.47 (t, 1H, J¼6.3 Hz), 2.79–3.03 (m, 3H), 3.28 (dd,
1H, J¼4.4, 12.5 Hz), 3.35 (br s, 1H), 3.74–3.87 (m, 1H),
4.25 (d, 1H, J¼9.1 Hz), 7.17–7.47 and 7.67–7.77 (m, 13H);
13C NMR (75 MHz, CDCl3) d 21.7, 10.4, 28.0, 38.5, 50.3,
50.8, 53.4, 55.1, 73.2, 81.9, 120.0, 120.3, 125.8, 126.1,
126.2, 127.5, 128.2, 128.6, 128.9, 140.2, 141.1, 144.2,
148.7, 149.2, 174.2. HRESMS m/z 656.2676 (MþNa)þ
(C33H43N5O4SSiþNaþ requires 656.2703).
1
1450 cm21; H NMR (300 MHz, CDCl3) d 0.03 (s, 9H),
1.00–1.10 (m, 2H), 1.26 (s, 9H), 1.60–1.70 (m, 1H), 1.95–
2.05 (m, 1H), 2.85–2.95 (m, 2H), 3.04 (dd, 1H, J¼1.7,
10.7 Hz), 3.12 (dd, 1H, J¼4.4, 9.7 Hz), 3.30 (d, 1H,
J¼9.7 Hz), 3.85–3.95 (m, 1H), 6.37 (d, 1H, J¼10.3 Hz),
7.10–7.20 (m, 1H), 7.20–7.50 (m, 8H), 7.50–7.60 (m, 2H),
7.60–7.65 (m, 1H), 7.75–7.80 (m, 1H); 13C NMR (75 MHz,
CDCl3) d 21.8, 10.7, 28.0, 38.5, 50.3, 53.5, 56.7, 59.4, 76.0,
81.4, 120.0, 120.4, 126.7, 127.0, 127.5, 127.6, 127.7, 128.2,
128.5, 128.7, 128.9, 139.4, 141.9, 142.4, 145.5, 148.1,
176.3. HRESMS m/z 591.2675 (MH)þ (C33H43N2O4SSi
requires 591.2713).
1.1.14. t-Butyl (2S,4S)-5-[N0,N00-bis(benzyloxycarbonyl)-
guanidino]-2-N-(9-phenyl-9H-fluoren-9-yl)amino-4-N-
(2-trimethylsilylethanesulfonyl)aminopentanoate ((S,S)-
26). To a solution of compound (S,S)-25 (100 mg,
0.16 mmol) in THF (9 mL) was added triphenylphosphine
(55 mg, 0.21 mmol) and water (170 mL, 9.4 mmol). The
reaction mixture was refluxed for 20 h, the solvent was
evaporated and the residue was dried under vacuum. The
latter was dissolved in DMF (1.8 mL) and S-methyl N,N0-
bis(benzyloxycarbonyl)isothiourea (68 mg, 0.19 mmol),
mercuric chloride (52 mg, 0.19 mmol) and triethylamine
(66 mL, 0.47 mmol) were added. The reaction mixture was
stirred for 84 h at rt, diluted with ethyl acetate (25 mL) and
filtered. The filtrate was washed with a 10% aqueous citric
acid solution (3£15 mL) and then with saturated aqueous
NaCl (2£15 mL), dried over MgSO4 and evaporated under
vacuum. Chromatography of the residue on silica gel (ethyl
acetate–heptane 1:3) afforded compound (S,S)-26 as a pasty
white solid (116 mg, 80%): [a]2D4 255 (c 0.51, CHCl3); IR
Compound (S,R)-24 (25 mg, 17%): [a]2D2 þ18 (c 0.66,
1
CHCl3); IR (film) 3271, 2926, 2854, 1735, 1450 cm21; H
NMR (250 MHz, CDCl3) d 0.00 (s, 9H), 0.85–0.95 (m, 2H),
1.29 (s, 9H), 1.50–1.70 (m, 1H), 1.95–2.10 (m, 1H), 2.58 (t,
1H, J¼9.0 Hz), 2.80–2.90 (m, 2H), 3.32 (dd, 1H, J¼1.8,
9.7 Hz), 3.52 (dd, 1H, J¼6.4, 9.0 Hz), 4.02 (d, 1H,
J¼8.9 Hz), 4.05–4.20 (m, 1H), 7.05–7.45 (m, 8H), 7.50–
7.60 (m, 3H), 7.60–7.75 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 21.9, 10.8, 28.0, 40.0, 49.5, 52.1, 55.1, 60.3, 76.5,
80.5, 120.0, 120.3, 126.4, 126.8, 127.5, 127.6, 127.9, 128.1,
128.6, 128.7, 128.8, 140.3, 141.0, 142.6, 146.9, 147.6,
174.3. HRESMS m/z 591.2714 (MH)þ (C33H43N2O4SSi
requires 591.2713).
1.1.13. t-Butyl (2S,4S)- and (2S,4R)-5-azido-2-N-(9-
phenyl-9H-fluoren-9-yl)amino-4-N-(2-trimethylsilyl-
ethanesulfonyl)aminopentanoate ((S,S)-25 and (S,R)-25,
respectively). To a solution of compound (S,RS)-17
(870 mg, 1.47 mmol) in DMF (12 mL) were successively
added under argon at rt solid sodium azide (400 mg,
6.15 mmol) and boron trifluoride etherate (0.75 mL,
6.1 mmol). The mixture was heated at 65 8C for 80 h, and
after cooling to rt, water (120 mL) was added. The solution
was extracted with ethyl acetate (3£200 mL), the organic
extracts were combined, dried over MgSO4 and evaporated.
A first purification of the residue by column chromato-
graphy on silica gel (ethyl acetate–heptane 1:7) provided
(S,S)-25 and (S,R)-25 as a mixture (760 mg, ,75%)
contaminated with a small amount of the aminoproline
derivative 24. The isomeric azides were partially separated
by careful chromatography on silica gel using ethyl
acetate–toluene (1:18) as eluting solvent. Pure (S,S)-25
(major diastereomer) was finally obtained by preparative
HPLC of the enriched fraction on a PrepPak Deltapak C18
1
(film) 3333, 2954, 1729, 1642 cm21; H NMR (250 MHz,
CDCl3) d 0.04 (s, 9H), 1.05–1.15 (m, 2H), 1.21 (s, 9H),
1.50–1.60 (m, 1H), 1.65–1.80 (m, 1H), 2.71 (dd, 1H,
J¼3.6, 8.0 Hz), 2.80–3.05 (m, 3H), 3.35–3.45 (m, 1H),
3.60–3.70 (m, 2H), 5.09 (s, 2H), 5.17 (d, 1H, J¼12.0 Hz),
5.25 (d, 1H, J¼12.0 Hz), 7.10–7.50 (m, 21H), 7.60–7.70
(m, 3H), 8.55 (t, 1H, J¼5.3 Hz), 11.7 (br s, 1H). 13C NMR
(62.5 MHz, CDCl3) d 21.9, 10.3, 27.9, 35.6, 44.0, 49.7,
51.9, 54.2, 67.3, 68.4, 73.3, 82.1, 120.0, 120.4, 126.0, 126.1,
126.4, 127.5, 128.0, 128.1, 128.2, 128.3, 128.5, 128.6,
128.7, 128.8, 128.9, 129.9, 134.6, 136.7, 140.2, 141.3,
143.5, 147.8, 148.4, 153.7, 156.4, 163.6, 173.6. HRESMS
m/z 940.3763 (MþNa)þ (C50H59N5O8SSiþNaþ requires
940.3751).
1.1.15. t-Butyl (2S,4R)-5-[N0,N00-bis(benzyloxycarbonyl)-
guanidino]-2-N-(9-phenyl-9H-fluoren-9-yl)-4-N-(2-tri-
methylsilylethanesulfonyl)-2,4-diaminopentanoate
((S,R)-26). Following the same procedure as for the
preparation of (S,S)-27, compound (S,R)-25 (156 mg,
0.25 mmol) in THF (18 mL) was refluxed for 20 h in the
presence of triphenylphosphine (112 mg, 0.43 mmol) and
water (350 mL, 19.4 mmol). After evaporation, the residue,
dissolved in DMF (3 mL), was treated with S-methyl N,N0-
bis(benzyloxycarbonyl)isothiourea (108 mg, 0.3 mmol),
mercuric chloride (82 mg, 0.3 mmol) and triethylamine
(105 mL, 0.75 mmol) and the reaction mixture was stirred
for 60 h at rt. Work up as before followed by chromato-
graphy of the residue on silica gel (ethyl acetate–heptane
1:5) provided compound (S,R)-26 as a pasty white solid
(125 mg, 51%): [a]2D3 238 (c 1.04, CHCl3); IR (film) 3331,
˚
cartridge (15 mm, 100 A, 47£250 mm) using 35:65 isocratic
H2Oþ0.1% CH3CO2H/CH3CNþ0.1% CH3CO2H: [a]D25
2134 (c 1.0, CHCl3); IR (film) 3286, 2926, 2103, 1728,
1
1449 cm21; H NMR (300 MHz, CDCl3) d 0.08 (s, 9H),
1.05–1.15 (m, 2H), 1.25 (s, 9H), 1.50–1.60 (m, 1H), 1.70–
1.80 (m, 1H), 2.65–2.75 (m, 1H), 2.85–3.05 (m, 2H),
3.08 (dd, 1H, J¼6.1, 12.4 Hz), 3.18 (dd, 1H, J¼5.8,
12.4 Hz), 3.45–3.60 (m, 1H), 7.20–7.50 (m, 11H), 7.70–
7.80 (m, 2H); 13C NMR (75 MHz, CDCl3) d 21.8, 10.6,
28.0, 35.9, 50.0, 52.4, 54.2, 54.5, 73.3, 82.0, 120.1, 120.4,
126.0, 126.2, 126.4, 127.6, 128.2, 128.3, 128.8, 129.0,
140.3, 141.3, 143.6, 147.9, 148.5, 173.6. HRESMS m/z
656.2727 (MþNa)þ (C33H43N5O4SSiþNaþ requires
656.2703).
1
1729, 1641 cm21; H NMR (250 MHz, CDCl3) d 0.04 (s,

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L. Saniere et al. / Tetrahedron 60 (2004) 5889–5897
5896
9H), 1.00–1.10 (m, 2H), 1.19 (s, 9H), 1.40–1.60 (m, 1H),
1.60–1.80 (m, 1H), 2.30–2.45 (m, 1H), 2.75–3.00 (m, 3H),
3.25–3.30 (m, 1H), 3.80–3.95 (m, 1H), 5.10 (s, 2H), 5.18
(d, 1H, J¼12.1 Hz), 5.24 (d, 1H, J¼12.1 Hz), 5.43 (d, 1H,
J¼7.0 Hz), 7.20–7.50 (m, 21H), 7.60–7.70 (m, 2H), 8.40
(t, 1H, J¼5.7 Hz), 11.7 (br s, 1H); 13C NMR (75 MHz,
CDCl3) d 21.8, 10.5, 28.0, 39.9, 44.1, 50.0, 51.9, 53.5,
67.3, 68.5, 73.2, 81.6, 120.0, 120.3, 125.7, 126.2, 126.6,
127.4, 128.1, 128.4–128.8, 134.6, 136.7, 140.3, 141.1,
144.2, 148.7, 149.4, 153.6, 157.3, 163.4, 174.4. HRESMS
m/z 940.3741 (MþNa)þ (C50H60N5O8SSiþNaþ requires
940.3751).
Acknowledgements
We thank the French Ministry of Education (MENRT) and
the Institut de Chimie des Substances Naturelles for
fellowships (L.S. and L.L.). The support and sponsorship
concerted by COST Action D24 ‘Sustainable Chemical
Processes: Stereoselective Transition Metal-Catalysed
Reactions’ are kindly acknowledged.
References and notes
1.1.16. t-Butyl (2S,40S)-3-[20-N-(benzyloxycarbonyl)-
aminoimidazolidin-40-yl]-2-N-(9-phenyl-9H-fluoren-9-
yl)aminopropanoate ((S,S)-27). A mixture of compound
(S,S)-26 (281 mg, 0.31 mmol) and cesium fluoride (141 mg,
0.93 mmol) in DMF (3.5 mL) was heated at 90 8C for 24 h.
Water (50 mL) was added and the solution was extracted
with ethyl acetate (3£50 mL). The organic extracts were
combined, dried over MgSO4 and evaporated leaving a
crude product which was purified by column chromato-
graphy on silica gel (heptane–ethyl acetate 1:1), affording
compound (S,S)-27 as a viscous oil which slowly solidified
(65 mg, 35%). HPLC of an aliquot on a Waters C18
Symmetry column (4.6£250 mm) using waterþ0.1%
CH3CO2H/CH3CNþ0.1% CH3CO2H as eluting solvents
(85:15 to 12:88 gradient over 40 min; 1 mL/min flow rate)
indicated that compound (S,S)-27 was 99% pure: [a]2D3 296
(c 0.84, CHCl3); IR (film) 3389, 2929, 1724, 1657,
1. Bursavich, M. G.; Rich, D. H. J. Med. Chem. 2002, 45,
541–558.
2. The Practice of Medicinal Chemistry; Wermuth, C. G., Ed.;
Academic Press: London, 1996; Chapter 14.
3. Lundquist, J. T.; Orwig, K. S.; Dix, T. A. J. Org. Chem. 1999,
64, 9265–9267.
4. Ulhaq, S.; Chinje, E. C.; Naylor, M. A.; Jaffar, M.; Stratford,
I. J.; Threadgill, M. D. Bioorg. Med. Chem. 1999, 7,
1787–1796.
5. Lee, Y.; Marletta, M. A.; Martasek, P.; Roman, L. J.; Masters,
B. S. S.; Silverman, R. B. Bioorg. Med. Chem. 1999, 7,
1097–1104.
6. Shearer, B. G.; Lee, S.; Franzmann, K. W.; White, H. A. R.;
Sanders, D. C. J.; Kiff, R. J.; Garvey, E. P.; Furfine, E. S.
Bioorg. Med. Chem. Lett. 1997, 7, 1763–1768.
7. St Laurent, D. R.; Balasubramanian, N.; Han, W. T.; Trehan,
A.; Federici, M. E.; Meanwell, N. A.; Wright, J. J.; Seiler,
S. M. Bioorg. Med. Chem. 1995, 3, 1145–1156.
8. (a) Horii, S.; Kameda, Y. J. Antibiot. 1968, 21, 665–667.
(b) Higashide, E.; Hatano, K.; Shibata, M.; Nakazawa, K.
J. Antibiot. 1968, 21, 126–137. (c) Asai, M.; Muroi, M.;
Sugita, N.; Kawashima, H.; Mizuno, K.; Miyake, A.
J. Antibiot. 1968, 21, 138–146.
1
1622 cm21; H NMR (300 MHz, CDCl3) d 1.18 (s, 9H),
1.50–1.70 (m, 2H), 2.44–2.54 (m, 1H), 3.09 (dd, 1H,
J¼7.3, 9.3 Hz), 3.22 (br s, 1H), 3.69 (t, 1H, J¼9.3 Hz),
4.01–4.14 (m, 1H), 5.05 (d, 1H, J¼12.6 Hz), 5.13 (d, 1H,
J¼12.6 Hz), 6.56–6.84 (br s, 1H), 7.13–7.45 (m, 16H),
7.65–7.75 (m, 2H), 7.80–8.20 (br s, 1H); 13C NMR
(75 MHz, CDCl3) d 28.0, 41.1, 48.1, 51.7, 53.9, 66.5,
73.1, 81.6, 120.0, 120.4, 125.1, 126.2, 126.3, 127.4, 127.7,
127.9, 128.1, 128.4–128.5, 128.9, 137.6, 140.2, 141.1,
144.3, 148.8, 149.0, 163.2, 164.8, 174.4. HRESMS m/z
603.3009 (MH)þ (C37H39N4O4 requires 603.2971).
9. (a) Hamada, M.; Kondo, J.; Yokoyama, T.; Miura, K.; Iinuma,
K.; Yamamoto, H.; Maeda, K.; Takeuchi, T.; Umezawa, H.
J. Antibiot. 1974, 27, 81–83. (b) Iinuma, K.; Kondo, S.;
Maeda, K.; Umezawa, H. J. Antibiot. 1975, 28, 613–615.
(c) Iinuma, K.; Kondo, S.; Maeda, K.; Umezawa, H. Bull.
Chem. Soc. Jpn 1977, 50, 1850–1854.
1.1.17. t-Butyl (2S,40R)-3-[20-N-(benzyloxycarbonyl)-
aminoimidazolidin-40-yl]-2-N-(9-phenyl-9H-fluoren-9-
yl)aminopropanoate ((S,R)-27). Following the same
procedure as for the preparation of (S,S)-27, compound
(S,R)-26 (119 mg, 0.13 mmol) in DMF (1.5 mL) was treated
with cesium fluoride (60 mg, 0.4 mmol) for 24 h at 90 8C.
Work-up and purification as before afforded compound
(S,R)-27 as a pasty solid (26 mg, 33%). HPLC analysis of an
aliquot under the same conditions as for (S,S)-27 showed
(S,R)-27 to be 98% pure: [a]2D3 2100 (c 0.9, CHCl3); IR
´ ´
10. Garcia, A.; Vazquez, M. J.; Quin˜oa, E.; Riguera, R.; Debitus,
C. J. Nat. Prod. 1996, 59, 782–785.
11. Tsuji, S.; Kusumoto, S.; Shiba, T. Chem. Lett. 1975,
1281–1284.
12. See references cited in: Dodd, D. S.; Kozikowski, A. P.
Tetrahedron Lett. 1994, 35, 977–980.
13. Guillerm, D.; Lavrador, K.; Guillerm, G. Synth. Commun.
1995, 25, 877–882.
14. Dappen, M. S.; Pellicciari, R.; Natalini, B.; Monahan, J. B.;
Chiorri, C.; Cordi, A. A. J. Med. Chem. 1991, 34, 161–168.
15. For a review of a-allyglycine chemistry, see: Rutjes, F. P. J.
T.; Wolf, L. B.; Schoemaker, H. E. J. Chem. Soc., Perkin
Trans. 1 2000, 4197–4212.
1
(film) 2925, 1727, 1652, 1622 cm21; H NMR (250 MHz,
CDCl3) d 1.18 (s, 9H), 1.50–1.65 (m, 1H), 1.65–1.80 (m,
1H), 2.40–2.50 (m, 1H), 3.01 (dd, 1H, J¼7.7, 9.7 Hz), 3.36
(t, 1H, J¼9.7 Hz), 3.95–4.10 (m, 1H), 5.16 (d, 1H,
J¼12.5 Hz), 5.23 (d, 1H, J¼12.5 Hz), 7.15–7.45 (m,
16H), 7.65–7.75 (m, 2H); 13C NMR (75 MHz, CDCl3) d
28.0, 40.4, 47.6, 53.4, 54.5, 67.8, 73.2, 81.8, 120.0, 120.3,
125.2, 126.2, 126.8, 127.5, 128.2, 128.3, 128.6, 128.7,
136.1, 140.4, 141.1, 143.8, 148.4, 149.2, 159.8, 161.1,
174.3. HRESMS m/z 603.3000 (MH)þ (C37H39N4O4)
requires 603.2971).
16. (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Org. Chem.
1991, 56, 6744–6746. (b) Evans, D. A.; Faul, M. M.;
Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742–2753.
17. For reviews, see: (a) Dauban, P.; Dodd, R. H. Synlett 2003,
1571–1586. (b) Mu¨ller, P.; Fruit, C. Chem. Rev. 2003, 103,
2905–2919.
18. Dauban, P.; Dodd, R. H. J. Org. Chem. 1999, 64, 5304–5307.
19. White, R. D.; Wood, J. L. Org. Lett. 2001, 3, 1825–1827.

`
L. Saniere et al. / Tetrahedron 60 (2004) 5889–5897
5897
20. Sudau, A.; Mu¨nch, W.; Bats, J. W.; Nubbemeyer, U. Chem.
Eur. J. 2001, 7, 611–621.
CDCl3) d 0.09 (s, 9H), 1.05–1.15 (m, 2H), 1.41 (s, 9H), 1.90–
2.20 (m, 2H), 2.30–2.40 (m, 1H), 2.70–2.80 (m, 1H), 2.85–
2.95 (m, 2H), 3.30–3.40 (m, 1H), 3.77 (dd, 1H, J¼6.8,
9.4 Hz), 6.08 (d, 1H, J¼7.2 Hz), 7.05–7.45 (m, 13H); 13C
NMR (75 MHz, CDCl3) d 21.8, 10.7, 22.2, 28.0, 46.1, 48.8,
56.2, 57.6, 76.3, 81.6, 120.2, 120.3, 126.0, 126.7, 127.8, 127.9,
128.0, 128.6, 129.0, 129.1, 140.1, 140.9, 141.5, 145.7, 146.9,
173.3.
21. Schricker, B.; Thirring, K.; Berner, H. Bioorg. Med. Chem.
Lett. 1992, 2, 387–390.
`
22. Leman, L.; Saniere, L.; Dauban, P.; Dodd, R. H. Arkivoc 2003,
126–134.
23. (a) Lodder, M.; Wang, B.; Hecht, S. M. Tetrahedron 2000, 56,
´
9421–9429. (b) Bergmeier, S. C.; Cobas, A. A.; Rapoport, H.
J. Org. Chem. 1993, 58, 2369–2376.
´
29. Knouzi, N.; Vaultier, M.; Carrie, R. Bull. Soc. Chim. Fr. 1985,
815–819.
24. (a) Armstrong, A.; Brackenridge, I.; Jackson, R. F. W.; Kirk,
J. M. Tetrahedron Lett. 1988, 29, 2483–2486. (b) Gosselin, F.;
Lubell, W. D. J. Org. Chem. 1998, 63, 7463–7471.
`
25. Dauban, P.; Saniere, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem.
Soc. 2001, 123, 7707–7708.
30. (a) Weinhardt, K.; Beard, C. C.; Dvorak, C.; Marx, M.;
Patterson, J.; Roszkowski, A.; Schuler, M.; Unger, S. H.;
Wagner, P. J.; Wallach, M. B. J. Med. Chem. 1984, 27,
616–627. (b) Su, W. Synth. Commun. 1996, 26, 407–413.
31. He, H.; Williamson, R. T.; Shen, B.; Graziani, E. I.; Yang,
H. Y.; Sakya, S. M.; Petersen, P. J.; Carter, G. T. J. Am. Chem.
Soc. 2002, 124, 9729–9736.
26. Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.
J. Am. Chem. Soc. 1993, 115, 5328–5329.
27. Dauban, P.; Dodd, R. H. Tetrahedron Lett. 1998, 39,
5739–5742.
32. Vermeij, T. A. C.; Edelbroek, P. M. J. Chromatography B
1998, 716, 233–238.
28. A second minor (,10%) product was co-eluted with this
compound whose NMR spectra indicated that it corresponded
to the azetidine resulting from aziridine ring-opening at the
C-4 position. ESMS m/z 591 (MH)þ; 1H NMR (250 MHz,
33. Farquhar, D.; Cherif, A.; Bakina, E.; Nelson, J. A. J. Med.
Chem. 1998, 41, 965–972.