Synthesis and biological evaluation of conformationally constrained analogues of the antitubercular agent ethambutol

Article abstract of DOI:10.1016/j.bmc.2007.05.064

Three (S)-prolinol-derived conformationally restricted analogues of the antitubercular agent ethambutol were prepared and tested against Mycobacterium tuberculosis.

Full text of DOI:10.1016/j.bmc.2007.05.064

Bioorganic & Medicinal Chemistry 15 (2007) 5866–5876
Synthesis and biological evaluation of conformationally
constrained analogues of the antitubercular agent ethambutol
a
a,
a
*
´
Vanessa Faugeroux, Yves Genisson, Yahya Salma,
Patricia Constantb and Michel Baltasa
a
`
´
´ ˆ
Laboratoire de Synthese et Physicochimie de Molecules d’Interet Biologique, UMR 5068,
Universite´ Paul Sabatier, 31062 Toulouse, Cedex 9, France
bInstitut de Pharmacologie et de Biologie Structurale, CNRS UMR 5098, 205 route de Narbonne,
33077 Toulouse, Cedex 4, France
Received 27 February 2007; revised 16 May 2007; accepted 30 May 2007
Available online 2 June 2007
Abstract—Three (S)-prolinol-derived conformationally restricted analogues of the antitubercular agent ethambutol were prepared
and tested against Mycobacterium tuberculosis.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
still hampered by lack of structural data concerning its
enzymatic targets.
The World Health Organization’s reports on tuberculosis
(TB) are alarming.1 Almost 9 million new cases occurred
in 2004 and TB kills nearly 2 million people over the world
every year. It is estimated that one-third of the world’s
population is infected by Mycobacterium tuberculosis,
the bacillus responsible for TB. Moreover, the global
TB incidence is growing at 1% a year due to a rapid in-
crease in Africa. Indeed, association with HIV has con-
tributed to the resurgence of this curable disease. The
worldwide emergence of multi-drug resistant TB is also
considered to aggravate the current pandemic.
The possibility that EMB could act as a cation chelate is
inherent to its discovery and historically led to the intro-
duction of the hydroxyl groups in the b-position of the
amines. Although EMB has been shown to affect trace
metal metabolism in animal models, its hypothetical ac-
tion through mycobacteria cation inactivation is still
open to debate.4
In the context of the TB pandemic, the rather simple
structure of EMB renders the search for new analogues
attractive.
Ethambutol (EMB) (1) (Fig. 1) is a long-known front-
line antimycobacterial agent used against TB.2 Despite
its moderate bacteriostatic activity, this reliable and
well-accepted drug belongs to the standard anti-TB che-
motherapeutic regimen. About 10 years ago, EMB was
shown to inhibit the biosynthesis of the mycobacterial
cell wall.3 Its primary site of action is thought to be
the arabinosyltransferases responsible for building the
arabinan core of both the mycolyl-arabinogalactan
and lipoarabinomannan units. However, an accurate
understanding of its molecular mechanism of action is
2. Results and discussion
2.1. Design and synthetic approach
Reports concerning the structural optimization of EMB
have remained rather scarce for many years.5 Studies
have, however, elegantly led to the preparation of
EMB-saccharide and -iminosaccharide hybrid molecules
that proved, in fact, inactive.6 Lately, the occurrence of
a ‘better ethambutol’ has been systematically investi-
gated through virtual screening7 or a combinatorial ap-
proach.8 Several 1,2-diamines, such as SQ 109 (2),
displaying up to 14- to 35-fold improved in vitro antimy-
cobacterial potencies and promising pharmacokinetic
Keywords: Tuberculosis; Arabinosyltransferase; Ethambutol; Imine;
Reductive coupling; Hydrocyanation; Prolinol.
*
Corresponding author. Tel.: +33 (0) 561 55 62 99; fax: +33 (0) 561 55
82 45; e-mail: genisson@chimie.ups-tlse.fr
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.05.064

V. Faugeroux et al. / Bioorg. Med. Chem. 15 (2007) 5866–5876
5867
Me
HO
Me
H
N
N
N
H
N
H
N
H
NH
N
H
Me
OP
OH
HO
HO
5
6
7
OH
OH
Ethambutol (1)
Scheme 1. Targeted rigidified EMB analogues and their key imine
precursor.
Me
Me
H
N
Me
strained conformation.13,14 It thus seemed interesting
to evaluate the incidence on antimycobacterial activity
of such a specific structural alteration in light of the ori-
ginal ‘metal chelate hypothesis.’
N
H
SQ 109 (2)
A synthetic route was delineated allowing direct assem-
bly of the central 1,2-diamine pharmacophore. An origi-
nal prolinol-derived imine 6, ready for functionalization
at the 5-position of the pyrrolidine framework, was
selected as a pivotal intermediate.
N
N
SQ 775 (3)
Figure 1. Structure of ethambutol and of two analogues thereof.
2.2. Preparation of the pivotal imine
properties have thus been reported (Fig. 1).9 New cyclic
diamine scaffolds with in vivo activity against
M. tuberculosis have similarly been identified, like for
example the homopiperazine SQ 775 (3).10 Ferrocenyl
diamines also lacking the EMB hydroxymethyl
appendages have been recently reported.11 Despite being
conceptually derived from EMB, these achiral com-
pounds all contrast by their pronounced lipophilicity.
With regard to the preparation of the pivotal imine, we
chose the method described by V.L. Schramm and P.C.
Tyler for the synthesis of aza-C-nucleosides and devel-
oped by B.G. Davies for the synthesis of various
C-substituted iminosugars.15,16 This route relies on the
regioselective dehydrochlorination of an N-chloramine
intermediate. We selected two primary hydroxyl protect-
ing groups on the basis of their large steric bulk in order
to ensure an optimal level of regiocontrol: triphenylm-
ethyl (Tr) and tert-butyldiphenylsilyl (TBDPS).
We would like to report here our approach towards new
EMB analogues based on the identification of (S)-pro-
linol (4) as a rigidified equivalent of the key aminobuta-
nol fragment (Fig. 2). The relevancy of the prolinol
framework in the design of new antimycobacterial ara-
binosyltransferase inhibitors has already been demon-
strated by us and by J. Prandi.12 According to the
present strategy, either mono- or bicyclic conforma-
tion-restricted EMB analogues, such as 5 or 7, respec-
tively, could be targeted (Scheme 1). Such compounds
would retain several important structural features of
EMB: low molecular weight, reduced lipophilic charac-
ter and, for the bicyclic analogues, possibility of C2 sym-
metry. Additionally, the metal chelating capacity of
these analogues may be modulated due to their con-
O-Tr prolinol 8 was prepared using a previously
described 3-step procedure requiring intermediate
N-protection as a formamide.17 On the other hand,
the O-silylation of prolinol to give 9 was straightfor-
ward. The N-chlorination of 8 and 9 was efficiently
accomplished by the use of NCS in Et2O. The crucial
elimination step required careful optimization due to
the high sensitivity of the desired imines towards traces
of moisture and acids. Freshly prepared lithium tetram-
ethylpiperidine (LiTMP) was slowly added, at ꢀ78 ꢁC,
to the starting chloramine until complete consumption
of the latter. At this point, it was found that direct filtra-
tion of the reaction medium over neutral Al2O3 smoothly
delivered the imines in fairly good yield and appreciable
HO
Me
1
purity. As estimated by H NMR analysis of this crude
H
N
mixture, the regioisomeric ratio ranged from 80/20 for
the O-Tr derivative to 85/15 for O-TBDPS analogue.
Both thermodynamic imines were prepared separately
for identification by treatment of the corresponding
N-chloramine with DBU. If required, the desired imines
12 and 13 could be rapidly purified over neutral grade I
alumina and isolated in 88% and 73% yield, respectively,
as a mixture of isomers. On the basis of this study, we
carried out the rest of this work with the more readily
accessible imine 13 (Scheme 2).
N
H
Me
OH
Ethambutol (1)
Me
OH
Me
N
H
N
H
N
H
HO
2.3. Access to the semi-rigidified EMB analogues
(4)
HO
Functionalization of the 5-position of prolinol was then
undertaken by means of a hydrocyanation reaction of
Figure 2. Structural homology between ethambutol (1) and prolinol
(4).

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V. Faugeroux et al. / Bioorg. Med. Chem. 15 (2007) 5866–5876
15cis and 15trans to be separated by column chromatog-
i
iii
+
raphy. The relative configuration at C-5 was confirmed
by 1H NMR analysis. Differential NOE experiments
clearly demonstrated the cis relationship between H-2
and H-5 in 15cis and between H-2 and CH2OTBDPS
in 15trans. Finally, this 3-step sequence was efficiently
conducted without purification of the aminonitrile inter-
mediates affording the expected N-Boc aminonitriles
15cis and 15trans in 29% and 24% overall yield (an aver-
age of 81% combined yield for each step) from the start-
ing N-chloramine.
N
R1
N
H
(4)
N
N
OR2
OR2
OR2
OH
a
b
8: R1 = H, R2 = Tr
9: R1 = H, R2 = TBDPS
12a / 12b (80:20): R2 = Tr
13a / 13b (85:15): R2 = TBDPS
ii
10: R1 = Cl, R2 = Tr
11: R1 = Cl, R2 = TBDPS
Scheme 2. Reagents and conditions: (i) R = Tr: Ref. 17; for
R = TBDPS: TBDPSCl (1.1 equiv), Et3N (2.5 equiv), THF, rt, quant.;
(ii) NCS (1.1 equiv), Et2O, rt, 91% for R = Tr, 72% for R = TBDPS;
(iii) LiTMP (1.7 equiv), THF, ꢀ78 ꢁC, 88% for R = Tr, 73% for
R = TBDPS.
We then studied introduction of the required aminobut-
anol fragment. In principle, this can be achieved in two
ways: a) complete reduction of the nitrile to the corre-
sponding primary amine and reductive amination with
1-hydroxybutan-2-one or b) conversion of the nitrile
to an aldehyde and reductive amination with (S)-2-
aminobutan-1-ol.
derivative 13. The resulting nitriles were then well suited
for the branching of the missing aminobutanol unit via
conversion either to an aldehyde or an amine, followed
by reductive amination.
Treatment of the N-Boc aminonitriles 15cis or 15trans
by Raney Ni (5 bars H2, EtOH–NH3, rt) cleanly deliv-
ered the corresponding primary amines (58% or 67%
yield, respectively) (Scheme 3). However, because of
the expected lack of stereocontrol at the newly formed
asymmetric centre during the reductive amination with
1-hydroxybutan-2-one, we chose the alternative route.
Preliminary studies on a purified sample of imine 13
showed that treatment with TMSCN (1.5 equiv) in the
presence of Yb(OTf)3 (0.1 equiv) (CH2Cl2, 0 ꢁC, MS
˚
4 A) afforded the expected aminonitriles in 66% yield
as a 50/50 diastereoisomeric mixture (not shown).18
The same result was obtained using diethyl phosphoroc-
yanidate (DEPC) (1.5 equiv) and imidazole (1.5 equiv)
(THF, rt) (Scheme 3).19 Hydrocyanation product of
the minor imine 13b could not be detected. These condi-
tions were conveniently applied to the crude imines
allowing isolation of the aminonitriles in ca. 50% com-
bined yield from the N-chloramine. The N-protection
was achieved by introduction of a Boc group using a
large excess of Boc anhydride in a 1 M aqueous
NaOH/THF mixture at rt, allowing the two isomers
Access to the desired sensitive aminoaldehydes was se-
cured by action of DIBAL-H in a strongly apolar med-
ium followed by careful hydrolysis of the imine
intermediate. After meticulous optimization, it was
found that treatment with a simple saturated aqueous
solution of potassium hydrogen tartrate (pH 3–4) al-
lowed clean isolation of the expected N-Boc aminoalde-
hyde 17cis or 17trans (58% or 77% yield, respectively)
13a / 13b
i
iv
H
iii
NC
N
N
N
R
BOC
NH2
BOC
OTBDPS
O
OTBDPS
OTBDPS
14cis/14trans: R = H
17cis, from 15cis
16cis, from 15cis
ii
17trans, from 15trans
16trans, from 15trans
15cis/15trans: R = BOC
v
Me
Me
vi
N
H
N
NH
NH
OH
BOC
HO
OTBDPS
OH
19cis, from 18cis
19trans, from 18trans
18cis, from 17cis
18trans, from 17trans
Scheme 3. Reagents and conditions: (i) DEPC (1.5 equiv), imidazole (1.5 equiv), THF, rt; (ii) (Boc)2O (9.0 equiv), aqueous NaOH/THF, rt; 29% in
15cis and 24% in 15trans based on the starting N-chloramine 11; (iii) Raney Ni, 5b H2, EtOH–NH3, 58% in 16cis from 15cis and 67% in 16trans from
15trans; (iv) DIBAL-H (2.0 equiv), petroleum ether/toluene, ꢀ78 ꢁC then tartrate buffer, rt, 58% in 17cis from 15cis and 77% in 17trans from 15trans;
˚
(v) (S)-2-aminobutan-1-ol (1.1 equiv), NaBH(OAc)3 (1.4 equiv), 4 A MS, CH2Cl2, rt, 58% in 18cis from 17cis and 65% in 18trans from 17trans; (vi)
MeOH–HCl, rt, 85% in 19cis from 18cis and 86% in 19trans from 18trans.

V. Faugeroux et al. / Bioorg. Med. Chem. 15 (2007) 5866–5876
5869
(Scheme 3). Importantly, any epimerization was
avoided. The spectral data for the isomer 17trans were
in good agreement with those reported previously.20
tion, the Sm(0)/I2/Ti(Oi-Pr)4 system was found to allow
efficient and complete d,l selective coupling.23 These
conditions compare well in terms of stereoselectivity,
practicality and innocuousness with the few methods re-
ported to be useful with the same imine.24
Reductive amination with (S)-2-aminobutan-1-ol was
achieved better using sodium triacetoxyborohydride
than sodium cyanoborohydride, the latter giving rather
confused and poorly reproducible transformations.21
Thus, the expected aminoalcohol 18cis or 18trans was
formed in a stereospecific manner (58% or 65% yield,
respectively) under these smooth and neutral conditions
(Scheme 3).
When applied to the prolinol-derived imine 13 this pro-
cedure gave, as a single diastereoisomer, the expected
bipyrrolidine 23 in 20% yield, along with O-TBDPS pro-
linol (Scheme 5). While NMR analysis clearly indicated
the C2 symmetry of compound 23, NOE measurements
were unable to distinguish between (2S,20S) and
(2R,20R). We proposed the all-S configuration as it cor-
responds to the combination of the intermediate radical
species by the less hindered face (Scheme 6). The pres-
ence of an unsubstituted methylene a to the intermediate
radical species, likely to favour the concurrent dispro-
portionation pathway, may explain the lower efficiency
of this transformation in comparison to the model
study. The direct access to the bipyrrolidine framework
afforded by this highly reproducible procedure was
found to compensate its modest efficiency.
For the final deprotection step we selected conditions
avoiding an aqueous work up in view of the expected
high polarity of the EMB analogues. Action of HCl in
methanol at rt followed by treatment with DOWEX cat-
ion exchange resin cleanly delivered the targeted 1,2-
diamines (Scheme 3).
2.4. Access to the bipyrrolidine analogue of EMB
The most straightforward access to the targeted bipyrro-
lidine skeleton was the pinacol type coupling of pivotal
imine 13. However, procedures useful for the reductive
coupling of enolisable alkylimine are scarce, mainly
because of their sluggish reactivity and their tendency
to rather suffer simple reduction.
The final deprotection was again achieved by the action
of HCl in methanol at rt followed by treatment with
DOWEX cation exchange resin, cleanly delivering the
targeted bipyrrolidine EMB analogue 24 (Scheme 5).
2.5. Biological evaluation
R. Yanada reported the use of in situ generated SmI2 for
the reductive coupling of aromatic imines.22 These con-
ditions proved ineffective with aliphatic substrates and a
model study was conducted with the representative
imine 20 (Scheme 4). After considerable experimenta-
The antimycobacterial activities of our three EMB ana-
logues were evaluated against the M. tuberculosis H37Rv
strain (Fig. 3). The semi-rigid analogue 19cis exerted a
modest growth inhibition at concentrations of over
60 lg/mL, whereas MIC of EMB under the same condi-
tions is around 2 lg/mL. The second diastereoisomer
BnNH HNBn
NBn
H
NHBn
i
+
1,6
DMSO
DMSO
1,4
1,2
1
EMB (1)
EMB (1)
20
21
22
24
24
19trans
19trans
19cis
19cis
Scheme 4. Reagents and condition: Ti(Oi-Pr)4 (1.0 equiv), Sm(0) (1.1
equiv), I2 (0.1 equiv) DME, rt, 80% in 21 and 20% in 22.
0,8
0,6
0,4
0,2
0
i
ii
13a / 13b
N
H
N
H
N
H
N
H
OTBDPS
OH
HO
OTBDPS
23
24
0,1
1
10
100
1000
[ ] µg/ml
Scheme 5. Reagents and conditions: (i) Ti(Oi-Pr)4 (1.0 equiv), Sm(0)
(1.1 equiv), I2 (0.1 equiv) DME, rt, 20%; (ii) MeOH–HCl, rt, 66%.
Figure 3. Activity against M. tuberculosis H37Rv strain.
H
˚
S
S
˚
13a / 13b
N N
M M
N
H
N
H
H
OTBDPS
OTBDPS
OTBDPS
OTBDPS
23
Scheme 6. Proposed stereochemical course for the reductive coupling of imine 13.

5870
V. Faugeroux et al. / Bioorg. Med. Chem. 15 (2007) 5866–5876
19trans and the bicyclic analogue 24 did not display any
appreciable activity.
in parts per million (ppm) relative to residual solvent
peak and coupling constants are given in Hertz. Dou-
bled 13C chemical shifts correspond to signals with
Dd < 0.05 ppm. Infrared (IR) spectra were recorded on
a Perkin-Elmer FT-IR 1725X spectrometer. Mass spec-
trometry (MS) data were obtained on a ThermoQuest
TSQ 7000 spectrometer. High resolution mass spectra
(HRMS) were recorded on a ThermoFinnigan MAT
95 XL spectrometer. Optical rotations were measured
on a Perkin-Elmer model 241 spectrometer.
It seems likely that conformational restrictions pro-
foundly affected the activities of our analogues. This
might imply that the high degree of conformational flex-
ibility of EMB is critical for its overall activity against
mycobacteria. Interestingly, a pronounced gap in
growth inhibitory potency was observed between the
two diastereoisomeric derivatives 19cis and 19trans.
4.1.2. (S)-2-((tert-Butyldiphenylsilyloxy)methyl)pyrroli-
dine (9). To a solution of (S)-prolinol (4) (8.97 g,
88.7 mmol) in anhydrous THF (222.0 mL) under inert
atmosphere were successively added Et3N (31.0 mL,
223 mmol) and tert-butyl-diphenylchlorosilane (25.3 mL,
97.5 mmol). The reaction mixture was stirred overnight
before being filtered through Celite. THF was then
evaporated off under reduced pressure to afford 9
(30.2 g, quant.) as a yellow oil. An analytical sample
was purified by flash column chromatography on silica
3. Conclusion
We designed, synthesised and tested against
M. tuberculosis three conformationally constrained
EMB analogues. Our synthetic approach was based
on the pivotal prolinol-derived imine 13, prepared in
three steps with a 53% yield. Two semi-rigidified EMB
analogues 19cis and 19trans were accessed via a route
including imine hydrocyanation, conversion to an alde-
hyde and reductive amination. The bipyrrolidine scaf-
fold of the rigidified analogue 24 was secured by
means of an original pinacolic type reductive coupling
procedure based on the Sm(0)/I2/Ti(Oi-Pr)4 system. Bio-
logical evaluation revealed that only the semi-rigidified
EMB analogue 19cis retained some antimycobacterial
activity, displaying a 30-fold reduced potency as com-
pared to the parent drug. This synthetic work thus
paves the way for the preparation of other rigidified
EMB analogues in order to further evaluate the influ-
ence of the rigidity on the antimycobacterial activity
and provides new insights into the structure–activity
relationships with respect to the historical ‘metal chelate
hypothesis’.
gel (EtOAc/MeOH/NH4OH 97:1:2): colourless oil;
25
D
Rf = 0.35 (EtOAc/MeOH/NH4OH 97:1:2); ½aꢁ ꢀ1.6 (c
1.1, CHCl3); IR (neat) mmax = 3048, 2959, 2856 (C–H),
1
1425 (N–H), 1264 (C–O) cmꢀ1; NMR H (300 MHz,
CDCl3) d = 1.10 (s, 9H, SiC(CH3)3), 1.47–1.55 (m, 1H,
H-3), 1.70–1.86 (m, 3H, 2· H-4, H-30), 2.34 (sl, 1H,
NH), 2.83–3.04 (m, 2H, 2· H-5), 3.22–3.30 (m, 1H, H-
2), 3.65 (AB part of an ABX, 2J = 10.1 Hz,
3J = 6.0 Hz, 3J = 5.0 Hz, da ꢀ db = 16.8 Hz, 2H, CH2O-
Si), 7.37–7.47 (m, 6H, H-Ph), 7.68–7.72 (m, 4H, H-Ph)
ppm; NMR 13C (75 MHz, CDCl3) d = 19.2 (SiCq),
25.3 (C-4), 26.8 (SiC(CH3)3), 27.4 (C-3), 46.4 (C-5),
59.9 (C-2), 66.5 (CH2OSi), 127.6, 129.6 (CH-Ph), 133.6
(Cq-Ph), 135.5, 135.5 (CH-Ph) ppm; MS (DCI, NH3):
m/z = 340 (100) [M+H+]; HRMS (DCI, NH3): calcd
for C21H30NOSi [M+H+] 340.2097, found 340.2093.
4. Experimental
4.1. Chemistry
4.1.3. General procedure A: synthesis of N-chloramines.
N-chlorosuccinimide (1.1 equiv) was added to a 0.07 M
solution of O-protected prolinol (1.0 equiv) in anhy-
drous Et2O under inert atmosphere. The reaction mix-
ture was stirred until TLC analysis showed
disappearance of starting material (1–4 h) and was then
diluted with Et2O (30 mL/mmol). The organic phase was
successively washed with water (3· 15 mL/mmol) and
brine, dried with Na2SO4, filtered and concentrated un-
der reduced pressure.
4.1.1. General methods. Unless otherwise stated, all reac-
tions requiring anhydrous conditions were carried out
under nitrogen. The following solvents and reagents
were dried prior to use: CH2Cl2, MeOH (from calcium
hydride), 1,2-dimethoxyethane (DME), Et2O, petroleum
ether, THF, toluene (freshly distilled from sodium/ben-
zophenone), 2,2,6,6-tetramethylpiperidine (TMP), Et3N
(from calcium hydride, stored over potassium hydroxide
pellets). Analytical thin layer chromatography (TLC)
was performed using Merck silica gel 60 F254 precoated
plates. Chromatograms were observed under UV light
and/or were visualised by heating plates that were
dipped in 10% phosphomolybdic acid in ethanol or
Dragendorff reagent. Standard column chromatography
was performed with SDS 70–200 lm silica gel or Merck
70–230 mesh neutral alumina (Brockman grade I). Flash
column chromatography was carried out with SDS 35–
70 lm silica gel. NMR spectroscopic data were obtained
with Bruker AC 250, Advance 300, ARX 400 and Ad-
4.1.3.1. (S)-1-Chloro-2-(trityloxymethyl)pyrrolidine (10).
Compound 8 (330 mg, 0.96 mmol) was treated according
to general procedure A. The crude product was purified
by column chromatography on silica gel (2 g, pentane/
EtOAc 95:5) to give 10 (330 mg, 91%): colourless oil;
25
D
½aꢁ ꢀ65.1 (c 0.8, CHCl3); IR (neat) mmax = 3054, 2975,
2870 (C–H), 1595, 1489 (C@C), 1263 (C–O) cmꢀ1
;
1
NMR H (300 MHz, CDCl3) d = 1.65–1.94 (m, 3H, H-
3, 2· H-4), 2.04–2.15 (m, 1H, H-30), 2.98–3.07 (m, 1H,
H-5), 3.14–3.21 (m, 2H, H-2, H-50), 3.37–3.43 (m, 1H,
CH2O), 3.51–3.58 (m, 1H, CH02O), 7.24–7.36 (m, 9H, H-
Ph), 7.50–7.53 (m, 6H, H-Ph) ppm; NMR 13C (75 MHz,
CDCl3) d = 21.6 (C-4), 26.2 (C-3), 62.5 (C-5), 64.8
(CH2O), 71.4 (C-2), 86.6 (OCq), 127.0, 127.8, 128.8
1
vance 500 operating with H spectra at 250, 300, 400
and 500 MHz, respectively, 13C spectra at 63, 75, 100
and 125 MHz, respectively. Chemical shifts are quoted

V. Faugeroux et al. / Bioorg. Med. Chem. 15 (2007) 5866–5876
5871
(CH-Ph), 144.1 (Cq-Ph) ppm; MS (DCI, NH3): m/z = 378
4.1.4.2. (S)-2-((tert-Butyldiphenylsilyloxy)methyl)-3,4-
dihydro-2H-pyrrole (13a). Compound 11 (400 mg,
1.07 mmol) was treated according to general procedure
B. The 85:15 (13a/13b) regioisomeric ratio was deter-
(100) [M+H+].
4.1.3.2. (S)-2-((tert-Butyldiphenylsilyloxy)methyl)-1-chlo-
ropyrrolidine (11). Compound 9 (2.00 g, 5.87 mmol) was
treated according to general procedure A. The crude
product was purified by column chromatography on sil-
ica gel (11 g, petroleum ether/EtOAc 95:5) to give 11
1
mined by NMR H analysis (integrating the H-2 signal
of 13a and the CH2O signal of 13b). When required,
the crude imines were purified by column chromatogra-
phy on alumina (18 g, dehydrated by heating under vac-
uum before use, Et2O/EtOAc 100:0, 50:50 and 0:100) to
give a mixture of imines 13a and 13b (265 mg, 73%): col-
ourless oil, Rf = 0.54 (EtOAc/CH2Cl2 50:50), IR (neat)
(1.58 g, 72% from (S)-prolinol): colourless oil;
25
D
Rf = 0.32 (petroleum ether/EtOAc 95:5); ½aꢁ ꢀ60.7 (c
2.0, CHCl3); IR (neat) mmax = 3087, 3085, 2928, 2853
1
(C–H), 1112 (C–O) cmꢀ1; NMR H (300 MHz, CDCl3)
m
max = 3047, 2930, 2856 (C–H), 1622 (C@N), 1263 (C–
d = 1.08 (s, 9H, SiC(CH3)3), 1.71–1.93 (m, 3H, 2· H-4,
H-3), 2.03–2.11 (m, 1H, H-30), 2.97–3.03 (m, 1H, H-5),
3.10–3.17 (m, 1H, H-2), 3.48–3.53 (m, 1H, H-50), 3.68
O) cmꢀ1
.
Major regioisomer 13a. NMR 1H (250 MHz, CDCl3)
d = 1.03 (s, 9H, SiC(CH3)3), 1.77–1.99 (m, 2H, 2· H-
3), 2.45–2.68 (m, 2H, 2· H-4), 3.82 (AB part of an
2
3
(dd, J = 10.4 Hz, J = 6.3 Hz, 1H, CH2OSi), 3.92 (dd,
2J = 10.4 Hz, J = 4.3 Hz, 1H, CH02OSi), 7.38–7.47 (m,
3
6H, H-Ph), 7.69–7.72 (m, 4H, H-Ph) ppm; NMR 13C
(100 MHz, CDCl3) d = 19.3 (SiCq), 21.6 (C-4), 25.8
(C-3), 26.8 (SiC(CH3)3), 62.5 (C-5), 65.0 (CH2OSi),
72.7 (C-2), 127.6, 127.6, 129.5, 129.6 (CH-Ph), 133.5,
133.6 (Cq-Ph), 135.6, 135.6 (CH-Ph) ppm; MS (DCI,
NH3): m/z = 374 (100) [M+H+].
ABX, J = 10.1 Hz, J = 4.9 Hz, J = 4.0 Hz, da ꢀ db =
23,7 Hz, 2H, CH2OSi), 4.17–4.28 (m, 1H, H-2), 7.34–
7.42 (m, 6H, H-Ph), 7.65–7.68 (m, 5H, H-Ph, H-5)
ppm; NMR 13C (100 MHz, CDCl3) d = 19.5 (SiCq),
23.4 (C-3), 27.0 (SiC(CH3)3), 37.5 (C-4), 66.6 (CH2OSi),
74.7 (C-2), 127.8, 127.9, 129.8, 129.8 (CH-Ph), 133.8,
134.0 (Cq-Ph), 135.8, 135.9 (CH-Ph), 167.7 (C-5) ppm;
MS (DCI, NH3): m/z = 338 (100) [M+H+].
2
3
3
4.1.4. General procedure B: synthesis of kinetic imines.
To a 0.2 M solution of TMP (1.9 equiv) in anhy-
drous THF at 0 ꢁC and under inert atmosphere was
slowly added n-BuLi (1.6 M solution in hexane, 1.8
equiv). The mixture was allowed to react with stir-
ring for 30 min at this temperature. In another flask,
a 0.08 M solution of N-chloramine (1 equiv) in anhy-
drous THF was cooled to ꢀ78 ꢁC. The LiTMP solu-
tion was then added dropwise to the N-chloramine
(flow rate: 10 mL hꢀ1) until TLC analysis showed
disappearance of starting material. The reaction mix-
ture was then cannulated under inert atmosphere
onto an alumina pad (6 g/mmol, 70–230 mesh neutral
alumina Brockman grade I) and the products were
eluted with anhydrous THF (3· 5 mL/mmol). The
resulting THF solution was concentrated under
reduced pressure.
4.1.5. General procedure C: synthesis of thermodynamic
imines. DBU (1.05 equiv) was added to a 0.04 M solu-
tion of N-chloramine (1 equiv) in anhydrous Et2O at
room temperature and under inert atmosphere. The
mixture was stirred for 24 h before being filtered
through Celite. The solution was concentrated under re-
duced pressure.
4.1.5.1. 5-(Trityloxymethyl)-3,4-dihydro-2H-pyrrole (12b).
Compound 10 (100 mg, 0.27 mmol) was treated according
to general procedure C to give 12b (120 mg). The crude
1
1
imine was analysed by H NMR. H NMR (250 MHz,
CDCl3) d = 1.82–1.94 (m, 2H, 2· H-3), 2.69 (t, 2H,
3J = 13.2 Hz, 2· H-4), 3.79–3.88 (m, 2H, 2· H-2), 3.90 (s,
2H, CH2O), 7.20–7.33 (m, 9H, H-Ph), 7.44–7.48 (m, 6H,
H-Ph) ppm.
4.1.4.1. (S)-2-(Trityloxymethyl)-3,4-dihydro-2H-pyrrole
(12a). Compound 10 (401 mg, 1.06 mmol) was treated
according to general procedure B. The 80:20 (12a/12b)
4.1.5.2. 5-((tert-Butyldiphenylsilyloxy)methyl)-3,4-dihy-
dro-2H-pyrrole (13b). Compound 11 (100 mg, 0.27 mmol)
was treated according to general procedure C to give 13b
(116 mg). The crude imine was analysed by 1H NMR. 1H
NMR (250 MHz, CDCl3) d = 1.07 (s, 9H, SiC(CH3)3),
1.80–1.93 (m, 2H, 2· H-4), 2.61–2.70 (m, 2H, 2· H-3),
3.78–3.87 (m, 2H, H-2), 4.42 (s, 2H, CH2OSi), 7.34–
7.47 (m, 6H, H-Ph), 7.64–7.69 (m, 4H, H-Ph) ppm.
1
regioisomeric ratio was determined by NMR H analy-
sis (integrating the H-2 signal of 12a and the CH2O sig-
nal of 12b). The crude imines were purified by column
chromatography on alumina (22 g, dehydrated by heat-
ing under vacuum before use, Et2O/EtOAc 100:0, 50:50
and 0:100) to give a mixture of imines 12a and 12b
(320 mg, 88%): yellow oil; Rf = 0.50 (EtOAc/CH2Cl2
50:50).
4.1.6. (2S,5R) and (2S,5S)-2-((tert-Butyldiphenylsilyloxy)-
methyl)-5-cyanopyrrolidine (14cis/14trans). To a solution
of the crude imines 13a/13b (obtained from 1.07 mmol
of N-chloramine 11) in anhydrous THF (5.4 mL) under
inert atmosphere were added diethyl phosphorocyani-
date (215 lL, 1.60 mmol) and imidazole (109 mg,
1.60 mmol). The mixture was stirred for 1 h 30 min be-
fore evaporating off the THF under reduced pressure.
The residue was taken up in Et2O and filtered through
Florisil 60–100 mesh (4 g) to give a crude mixture of
diastereoisomeric aminonitriles 14cis/14trans (536 mg).
Major regioisomer 12a. NMR 1H (250 MHz, CDCl3)
d = 1.57-1.71 (m, 1H, H-3), 1.82–2.02 (m, 1H, H-30),
2.45–2.65 (m, 2H, 2· H-4), 3.20–3.31 (m, 2H, CH2O),
4.21–4.34 (m, 1H, H-2), 7.19–7.32 (m, 9H, H-Ph),
7.45–7.47 (m, 6H, H-Ph), 7.80 (s, 1H, H-5) ppm;
NMR 13C (75 MHz, CDCl3) d = 23.8 (C-3), 37.0 (C-4),
66.3 (CH2O); 73.0 (C-2), 86.8 (OCq), 126.8, 127.7,
128.7 (CH-Ph), 144.1 (Cq-Ph), 167.3 (C-5) ppm; MS
(DCI, NH3): m/z = 342 (100) [M+H+].

5872
V. Faugeroux et al. / Bioorg. Med. Chem. 15 (2007) 5866–5876
The crude products were then used in the next step. An
analytical sample of each diastereoisomer was purified
by flash column chromatography on silica gel (pen-
tane/EtOAc 80:20 to 65:35).
mixture of rotamers A and B) 1.09 (s, 9H, SiC(CH3)3),
1.35 (sl, 4.5H, OC(CH3)3B), 1.53 (sl, 4.5H, OC(CH3)3A),
1.95–2.39 (m, 4H, 2· H-4, 2· H-3), 3.62–4.02 (m, 3H,
H-2, CH2OSi), 4.41–4.51 (m, 0.5H, H-5A), 4.51–4.64 (m,
0.5H, H-5B), 7.37–7.45 (m, 6 H, H-Ph), 7.66–7.70 (m,
4H, H-Ph) ppm; NMR 13C (125 MHz, CDCl3) d = (as a
mixture of rotamers A and B) 19.2 (SiCq), 26.8
(SiC(CH3)3), 28.2 (OC(CH3)3), 29.3, 29.7, 30.0 (C-4A,
C-4B, C-3A, C-3B), 48.1 (C-5), 59.4 (C-2), 63.8, 64.6
(CH2OSiA, CH2OSiB), 81.2, 81.5 (OCqA, OCqB), 119.1,
119.3 (CNA, CNB), 127.7, 129.7 (CH-Ph), 133.3 (Cq-
Ph), 135.6 (CH-Ph), 153.1, 153.8 (C@OA, C@OB) ppm;
MS (DCI, NH3): m/z = 465 (100) [M+H+], 482 (45)
[M+NH4þ]; HRMS (DCI, NH3): calcd for C27H37N2O3Si
[M+H+] 465.2573, found 465.2573.
4.1.6.1. Less polar diastereoisomer. Rf = 0.20 (pen-
25
D
tane/EtOAc 80:20); ½aꢁ ꢀ18.2 (c 1.7, CHCl3); IR (neat)
m
max = 3470 (N–H), 3016, 2930 (C–H), 2207 (CꢂN),
1214 (C–O) cmꢀ1; NMR 1H (400 MHz, CDCl3)
d = 1.07 (s, 9H, SiC(CH3)3), 1.60–1.52 (m, 1H, H-3),
1.81–2.25 (m, 4H, 2· H-4, H-30, NH), 3.50–3.56 (m,
2H, H-2, CH2OSi), 3.63–3.68 (m, 1H, CH02OSi), 4.05
3
3
(dd, J = 7.3 Hz, J = 3.8 Hz, 1H, H-5), 7.38–7.47 (m,
6H, H-Ph), 7.65–7.71 (m, 4H, H-Ph) ppm; NMR 13C
(100 MHz, CDCl3) d = 19.2 (SiCq), 25.8 (C-3), 26.8
(SiC(CH3)3), 30.2 (C-4), 47.4 (C-5), 58.8 (C-2), 66.5
(CH2OSi), 121.6 (CN), 127.7, 129.8 (CH-Ph), 133.2,
133.2 (Cq-Ph), 135.5, 135.5 (CH-Ph) ppm; MS (DCI,
NH3): m/z = 365 (100) [M+H+], 382 (8) [M+NH4þ].
4.1.7.2. Diastereoisomer 15trans. Colourless oil;
25
D
Rf = 0.42 (pentane/EtOAc 90:10); ½aꢁ ꢀ70.8 (c 1.0,
CHCl3); IR (neat) mmax = 3071, 3051, 2959, 2931, 2858
(C–H), 2303 (CꢂN), 1704 (C@O), 1589, 1472 (C@C),
1
4.1.6.2. More polar diastereoisomer. Rf = 0.12 (pen-
1112 (C–O) cmꢀ1; NMR H (300 MHz, CDCl3) d = (as
25
D
1
tane/EtOAc 80:20); ½aꢁ +13.8 (c 1.5, CHCl3); NMR H
a 60/40 mixture of rotamers A and B) 1.07 (s, 9H,
SiC(CH3)3), 1.37 (s, 3.6H, OC(CH3)3B), 1.55 (s, 5.4H,
OC(CH3)3A), 2.14–2.54 (m, 4H, 2· H-4, 2· H3), 3.59–
3.65 (m, 0.4H, CH2OSiB), 3.68–3.72 (m, 1H, CH02OSi),
3.88 (dd, 2J = 10.2 Hz, 2J = 4.9 Hz, 0.6H, CH2OSiA),
3.95–3.99 (m, 0.4H, H-2B), 4.07–4.11 (m, 0.6H, H-2A),
4.47–4.50 (m, 0.6H, H-5A), 4.53–4.56 (m, 0.4H, H-5B),
7.37–7.48 (m, 6H, H-Ph), 7.61–7.66 (m, 4H, H-Ph) ppm;
NMR 13C (75 MHz, CDCl3) d = (as a mixture of rotamers
A and B) 19.2 (SiCq), 26.8 (SiC(CH3)3), 27.0 (C-3A), 27.7
(C-3B), 28.2 (OC(CH3)3B), 28.3 (OC(CH3)3A), 28.8 (C-
4B), 30.0 (C-4A), 48.2 (C-5B), 48.3 (C-5A), 58.4 (C-2B),
58.5 (C-2A), 64.0 (CH2OSiA), 64.2 (CH2OSiB), 81.2
(OCqB), 81.5 (OCqA), 119.1 (CNB), 119.4 (CNA), 127.7,
127.7, 129.7, 129.8 (CH-PhA, CH-PhB), 133.1, 133.2
(Cq-PhA, Cq-PhB), 135.4 (CH-Ph), 152.7, 153.2 (C@OA,
C@OB) ppm; MS (DCI, NH3): m/z = 465 (100) [M+H+],
482 (20) [M+NH4þꢁ; HRMS (DCI, NH3): calcd for
C27H37N2O3Si [M+H+] 465.2573, found 465.2572.
(400 MHz, CDCl3) d = 1.09 (s, 9H, SiC(CH3)3), 1.65–
1.75 (m, 1H, H-3), 1.89–1.97 (m, 1H, H-30), 2.13–2.17
(m, 2H, 2· H-4), 3.40 (pseudoqd, 3J = 7.0 Hz, 3J =
5.3 Hz, 1H, H-2), 3.67 (AB part of an ABX, 2J =
10.2 Hz, 3J = 6.9 Hz, 3J = 5.3 Hz, da ꢀ db = 7.2 Hz, 2H,
CH2OSi), 4.01 (dd, 3J = 6.5 Hz, 3J = 6.0 Hz, 1H,
H-5), 7.39–7.49 (m, 6H, H-Ph), 7.68–7.74 (m, 4H, H-Ph)
ppm; NMR 13C (100 MHz, CDCl3) d = 19.2 (SiCq),
26.8, 26.8 (C-3, SiC(CH3)3), 30.9 (C-4), 46.7 (C-5),
60.0 (C-2), 67.0 (CH2OSi), 121.8 (CN), 127.7, 129.7
(CH-Ph), 33.3 (Cq-Ph), 135.5, 135.6 (CH-Ph) ppm; MS
(DCI, NH3): m/z = 365 (100) [M+H+].
4.1.7. (2S,5S)-tert-Butyl 2-((tert-butyldiphenylsilyloxy)-
methyl)-5-cyanopyrrolidine-1-carboxylate (15cis) and (2S,
5R)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-5-
cyanopyrrolidine-1-carboxylate (15trans). To the crude
mixture of aminonitriles 14cis/14trans (obtained from
1.07 mmol of N-chloramine 11) in THF (10.0 mL) were
added 1 M aqueous NaOH (12.9 mL, 12.9 mmol) and
(Boc)2O (534 mg, 2.45 mmol). After stirring overnight
at room temperature, three additional portions of
(Boc)2O were added (3· 534 mg, 3· 2.45 mmol) over
3 h. Stirring was maintained for a further 1 h before
quenching the reaction by addition of water (50.0 mL).
The aqueous layer was extracted with Et2O (3·
125.0 mL) and the combined organic phases were
washed with brine, dried with Na2SO4, filtered and con-
centrated under reduced pressure. The crude mixture
was purified by flash column chromatography on silica
gel (49 g, pentane/EtOAc 95:5 to 80:20) to give the dia-
stereoisomers 15trans (142 mg, 29% from N-chloramine
11) and 15cis (120 mg, 24% from N-chloramine 11). The
relative configuration at C-5 for the two compounds was
determined by differential NOE experiments.
4.1.8. General procedure D: reduction of aminonitriles
into amines. To a 0.1 M solution of aminonitrile in
absolute ethanol saturated with gaseous NH3 was added
Raney Ni. The mixture was hydrogenated at 5 bars for
20 h before being first filtered through Celite, then
through a GELMAN 0.45 lm filter to remove traces
of catalyst. The solution was then concentrated under
reduced pressure.
4.1.8.1. (2S,5R)-tert-Butyl 5-(aminomethyl)-2-((tert-
butyldiphenylsilyloxy)methyl)pyrrolidine-1-carboxylate
(16cis). Compound 15cis (110 mg, 0.24 mmol) was trea-
ted according to general procedure D. The crude prod-
uct was purified by flash column chromatography on
silica gel (9 g, EtOAc/MeOH/NH4OH 97:1:2 to 94:4:2)
to give 16cis (65.7 mg, 58%): colourless oil; Rf = 0.53
(AE/MeOH 99:1 under a saturated atmosphere of
25
D
4.1.7.1. Diastereoisomer 15cis. Colourlessoil; Rf = 0.19
NH3); ½aꢁ ꢀ16.1 (c 1.0, CHCl3); IR (neat) mmax = 3414
25
D
(pentane/EtOAc 90:10); ½aꢁ +10.3 (c 2.0, CHCl3); IR
(N–H), 2955, 2932, 2852 (C–H), 1690 (C@O), 1471
(C@C), 1109 (C–O) cmꢀ1; NMR 1H (300 MHz, CDCl3)
d = 1.05 (s, 9H, SiC(CH3)3), 1.36 (sl, 9H, OC(CH3)3),
1.56–2.16 (m, 6H, NH2, 2· H-4, 2· H-3), 2.76 (AB part
(neat) mmax = 3071, 3050, 2960, 2931, 2858 (C–H), 2288
(CꢂN), 1703 (C@O), 1589, 1473 (C@C), 1112 (C–O)
cmꢀ1; NMR 1H (500 MHz, CDCl3) d = (as a 50/50

V. Faugeroux et al. / Bioorg. Med. Chem. 15 (2007) 5866–5876
5873
of an ABX, 2J = 12.8 Hz, 3J = 6.7 Hz, 3J = 5.4 Hz,
da ꢀ db = 55.5 Hz, 2H, CH2NH2), 3.46–4.01 (m, 4H,
H-5, H-2, CH2OSi), 7.33–7.46 (m, 6H, H-Ph), 7.61–
7.68 (m, 4H, H-Ph) ppm; NMR 13C (75 MHz, CDCl3)
d = 19.2 (SiCq), 26.8 (SiC(CH3)3), 27.4 (C-4 or C-3),
28.4 (OC(CH3)3), 29.6 (C-4 or C-3), 46.1 (CH2NH2),
59.6 (C-5), 61.2 (C-2), 64.9 (CH2OSi), 79.4 (OCq),
127.6, 129.6 (CH-Ph), 133.4 (Cq-Ph), 135.4, 135.5
(CH-Ph), 155.3 (C@O) ppm; MS (DCI, NH3):
m/z = 469 (100) [M+H+]; HRMS (DCI, NH3): calcd
for C27H41N2O3Si [M+H+] 469.2886, found 469.2883.
4.1.9.1. (2R,5S)-tert-Butyl 5-((tert-butyldiphenylsilyl-
oxy)methyl)-2-formylpyrrolidine-1-carboxylate (17cis).
Compound 15cis (59.0 mg, 127 lmol) was treated
according to general procedure E. The crude product
was filtered through Florisil 60–100 mesh (1 g, CH2Cl2)
to give 17cis (34.4 mg, 58%): colourless oil; Rf = 0.35
(pentane/EtOAc 90:10); NMR 1H (300 MHz, CDCl3)
d = (as a 60/40 mixture of rotamers A and B) 0.97 (s,
9H, SiC(CH3)3), 1.21–1.41 (m, 9H, OC(CH3)3), 1.80–
2.13 (m, 4H, 2· H-3, 2· H-4), 3.53–4.15 (m, 4H, H-2,
H-5, CH2OSi), 7.22–7.41 (m, 6H, H-Ph), 7.48–7.65 (m,
4H, H-Ph), 9.33 (d, 3J = 3.1 Hz, 0.6H, CHOA), 9.40
(sl, 0.4H, CHOB) ppm; NMR 13C (75 MHz, CDCl3)
d = (as a mixture of rotamers A and B) 19.2 (SiCq),
25.1 (C-3B or C-4B), 26.4 (C-3A or C-4A), 26.8, 26.9
(OC(CH3)3A, OC(CH3)3B), 27.1 (C-3A or C-4A), 27.9
(C-3B or C-4B), 28.3 (SiC(CH3)3), 59.4 (C-2B or C-5B),
59.6 (C-2A or C-5A), 64.4 (CH2OSiA), 64.6 (CH2OSiB),
66.2 (C-2 or C-5), 80.6, 80.8 (OCqA, OCqB), 127.7,
129.8 (CH-PhA, CH-PhB), 133.2 (Cq-Ph), 135.5, 135.6
(CH-PhA, CH-PhB), 153.9 (C@O), 201.1, 201.2 (CHOA,
CHOB) ppm.
4.1.8.2. (2S,5S)-tert-Butyl 5-(aminomethyl)-2-((tert-
butyldiphenylsilyloxy)methyl)pyr-rolidine-1-carboxylate
(16trans). Compound 15trans (159 mg, 0.34 mmol) was
treated according to general procedure D. The crude
product was purified by flash column chromatography
on silica gel (14 g, EtOAc/MeOH/NH4OH 97:1:2 to
88:10:2) to give 16trans (106 mg, 67%): colourless oil;
Rf = 0.35 (EtOAc/MeOH 99:1 under a saturated atmo-
25
D
max = 3370 (N–H), 3067, 3045, 2961, 2855 (C–H),
sphere of NH3); ½aꢁ ꢀ44.6 (c 1.3, CHCl3); IR (neat)
1691 (C@O), 1587, 1471 (C@C), 1110 (C–O) cmꢀ1
m
;
1
NMR H (300 MHz, CDCl3/D2O) d = (as a 65:35 mix-
ture of rotamers A and B) 1.05 (s, 9H, SiC(CH3)3),
1.28 (s, 5.9H, OC(CH3)3A), 1.46 (s, 3.1H, OC(CH3)3B),
1.65–2.22 (m, 4H, 2· H-4, 2· H-3), 2.56 (dd,
2J = 12.6 Hz, 3J = 8.0 Hz, 1H, CH2NH2), 2.89 (dd,
4.1.9.2. (2S,5S)-tert-Butyl 5-((tert-butyldiphenylsilyl-
oxy)methyl)-2-formylpyrrolidine-1-carboxylate (17trans).
Compound 15trans (50.0 mg, 108 lmol) was treated
according to general procedure E. The crude product
was filtered through Florisil 60–100 mesh (1 g, CH2Cl2)
to give 17trans (39.0 mg, 77%): colourless oil; Rf = 0.35
(pentane/EtOAc 90:10); NMR 1H (300 MHz, CDCl3)
d = (as a 55/45 mixture of rotamers A and B) 1.05 (s,
9H, SiC(CH3)3), 1.34 (s, 4H, OC(CH3)3B), 1.42 (s, 4H,
OC(CH3)3A), 1.83–2.41 (m, 4H, 2· H-3, 2· H-4), 3.62
3
2J = 12.6 Hz, J = 2.7 Hz, 0.35H, CH20 NH2B), 2.99 (dd,
3
2J = 12.6 Hz, J = 3.5 Hz, 0.65H, CH20 NH2A), 3.46 (dd,
2J = 9.4 Hz, 3J = 7.8 Hz, 0.65H, CH2OSiA), 3.65–3.99
(m, 3.35H, H-5, H-2, CH02OSi, CH2OSiB), 7.32–7.45
(m, 6H, H-Ph), 7.60–7.68 (m, 4H, H-Ph) ppm; NMR
13C (75 MHz, CDCl3) d = (as a mixture of rotamers A
and B) 19.1 (SiCqA), 19.1 (SiCqB), 25.8, 25.9, 26.0 (C-
4A, C-3A, C-4B or C-3B), 26.7 (SiC(CH3)3), 27.0 (C-4B
or C-3B), 28.2 (OC(CH3)3A), 28.4 (OC(CH3)3B), 44.0
(CH2NH2A), 44.8 (CH2NH2B), 58.7 (C-5A), 58.7 (C-
5B), 60.5 (C-2A), 60.6 (C-2B), 63.4 (CH2OSiB), 63.7
(CH2OSiA), 79.1 (OCqB), 79.2 (OCqA), 127.5, 127.6,
127.6, 129.4, 129.5 (CH-PhA, CH-PhB), 133.2, 133.4,
133.6 (Cq-PhA, Cq-PhB), 135.4, 135.4 (CH-Ph), 153.7
(C@OB), 153.9 (C@OA) ppm; MS (DCI, NH3):
m/z = 469 (100) [M+H+]; HRMS (DCI, NH3): calcd
for C27H41N2O3Si [M+H+] 469.2886, found 469.2884.
2
3
(dd, J = 9.9 Hz, J = 6.4 Hz, 0.45H, CH2OSiB), 3.67–
3.75 (m, 1H, CH2OSiA, CH02OSiB), 3.94 (dd,
3
2J = 10.2 Hz, J = 5.0 Hz, 0.55H, CH20 OSiA), 4.00–4.06
(m, 0.45H, H-5B), 4.13–4.21 (m, 1.10H, H-2A, H-5A),
3
3
4.30 (dpseudot, J = 9.4 Hz, J = 1.6 Hz, 0.45H, H-2B),
7.33–7.46 (m, 6H, H-Ph), 7.61–7.67 (m, 4H, H-Ph),
9.53 (d, 3J = 2.6 Hz, 0.55H, CHOA), 9.60 (d,
3J = 1.8 Hz, 0.45H, CHOB) ppm; NMR 13C (75 MHz,
CDCl3) d = (as a mixture of rotamers A and B) 19.2,
19.2 (SiCqA, SiCqB), 25.0, 26.6 (C-3A, C-3B or C-4A,
C-4B), 26.8, 26.8 (OC(CH3)3A, OC(CH3)3B), 27.0 (C-3
or C-4), 28.3 (SiC(CH3)3), 59.1, 59.3 (C-2A, C-2B or C-
5A, C-5B), 63.9, 64.3 (CH2OSiA+B), 65.7, 66.0 (C-2A,
C-2B or C-5A, C-5B), 80.4, 80.5 (OCqA, OCqB), 127.7,
127.7, 127.7, 127.8, 129.7, 129.7 (CH-PhA, CH-PhB),
133.2, 133.3, 133.3, 133.4 (Cq-PhA, Cq-PhB), 135.5,
135.5, 135.5 (CH-PhA, CH-PhB), 153.4, 154.3 (C@OA,
C@OB), 200.7, 200.7 (CHOA, CHOB) ppm.
4.1.9. General procedure E: synthesis of aminoaldehydes
from aminonitriles. A saturated potassium hydrogen tar-
trate solution (pH 3–4) was prepared by adding potas-
sium hydrogen tartrate (1.90 mg, 10.1 mmol) to water
(40.0 mL). DIBALH (2.0 equiv, as a 20% solution in tol-
uene) was added to a 0.1 M solution of aminonitrile (1.0
equiv) in anhydrous toluene/petroleum ether (2:1) at
ꢀ78 ꢁC and under inert atmosphere. The mixture was
stirred for 2 h 30 min at this temperature and saturated
potassium hydrogen tartrate solution (4· the volume of
the reaction mixture) was added. The reaction mixture
was allowed to warm up to 0 ꢁC and was then stirred
at this temperature for 5 h. The phases were separated
and the aqueous layer was extracted with Et2O (4·).
The combined organic phases were successively washed
with water and brine, dried with Na2SO4 and concen-
trated under reduced pressure.
4.1.10. General procedure F: reductive amination. To a
0.1 M solution of aldehyde (1.0 equiv) in anhydrous
CH2Cl2 under inert atmosphere were successively added
˚
4A molecular sieves, (S)-2-aminobutan-1-ol (1.1 equiv)
and NaBH(OAc)3 (1.4 equiv). After being stirred over-
night at room temperature, the reaction was quenched
by addition of solid NaHCO3 and a few drops of satu-
rated aqueous NaHCO3 solution. The mixture was
extracted directly in the reaction flask with EtOAc.
The combined organic phases were dried with Na2SO4
and concentrated under reduced pressure.

5874
V. Faugeroux et al. / Bioorg. Med. Chem. 15 (2007) 5866–5876
4.1.10.1. (2S,5R)-tert-Butyl 2-((tert-butyldiphenylsilyl-
(CH2OHA), 62.7 (CH2OHB), 63.5 (CH2OSiB), 63.8
(CH2OSiA), 79.2 (OCqB), 79.4 (OCqA), 127.6, 127.7,
127.7, 129.5, 129.6, 129.7 (CH-PhA, CH-PhB), 133.4,
133.5, 133.7 (Cq-PhA, Cq-PhB), 135.5, 135.5 (CH-PhA,
CH-PhB), 153.7 (C@OB), 154.1 (C@OA) ppm; MS
(DCI, NH3): m/z = 541 (100) [M+H+]; HRMS (DCI,
NH3): calcd for C31H49N2O4Si [M+H+] 541.3462,
found 541.3462.
oxy)methyl)-5-(((S)-1-hydroxy-butan-2-ylamino)methyl)pyr-
rolidine-1-carboxylate (18cis). Compound 17cis (34.4 mg,
73.7 lmol) was treated according to general procedure
C. The crude product was purified by flash column chro-
matography on silica gel (3 g, EtOAc/MeOH/NH4OH
98:0:2 to 97:1:2) to give 18cis (20.7 mg, 52%): colourless
25
D
oil; Rf = 0.46 (EtOAc/MeOH/NH4OH 97:1:2); ½aꢁ +0.4
(c 1.8, CHCl3); IR (neat) mmax = 3435 (O–H), 3071, 3050,
2962, 2931, 2858 (C–H), 1690 (C@O), 1589, 1473
4.1.11. General procedure G: final deprotection. 1 M
Methanolic HCl was prepared by slow addition of acetyl
chloride (344 lL, 5.00 mmol) to anhydrous MeOH
(5.0 mL) under inert atmosphere. A 0.05 M solution of
protected compound in 1 M methanolic HCl was stirred
overnight at room temperature under inert atmosphere.
The reaction mixture was then concentrated under
reduced pressure. The crude product was dissolved in
MeOH/water 2:1 (25 mL/mmol), acidic resin (Dowex
50 WX8-200, 12 g/mmol) was added, and the suspension
was stirred slowly for 1 h. The resin was then succes-
sively washed with water (500 mL/mmol) and MeOH
(150 mL/mmol), taken up in 3 M aqueous NH4OH (85
mL/mmol) and the mixture stirred slowly for 1 h. The
suspension was then filtered and the resin rinsed with
3 M aqueous NH4OH (850 mL/mmol). The resulting
solution was then concentrated to dryness under re-
duced pressure.
1
(C@C), 1112 (C–O) cmꢀ1; NMR H (300 MHz, CDCl3)
d = (as a 70/30 mixture of rotamers A and B) 0.84 (t,
3J = 7.5 Hz, 3 H, CH3), 1.06 (s, 9 H, SiC(CH3)3), 1.23–
1.48 (m, 11H, OC(CH3)3, CH3CH2), 1.72–2.13 (m, 4H,
2· H-4, 2· H-3), 2.44–2.55 (m, 1H, CHNH), 2.60–2.71
(m, 1H, CH2NH), 2.77 (dd, 2J = 11,6 Hz, 3J = 4.5 Hz,
2
3
1H, CH02NH), 3.20 (dd, J = 10.6 Hz, J = 6.8 Hz, 1H,
CH2OH), 3.48–3.64 (m, 0.3H, CH2OSiB), 3.54 (dd,
2J = 10.6 Hz, J = 4.0 Hz, 1H, CH02OH), 3.69–4.03 (m,
3
3.7H, H-5, H-2, CH02OSi, CH2OSiA), 7.34–7.45 (m, 6H,
H-Ph), 7.62–7.68 (m, 4H, H-Ph) ppm; NMR 13C
(75 MHz, CDCl3) d = 10.3 (CH3), 19.3 (SiCq), 24.2
(CH3CH2), 26.9 (SiC(CH3)3), 26.9, 28.1 (C-4, C-3), 28.4
(OC(CH3)3), 49.9 (CH2NH), 59.0 (C-5), 59.7 (C-2), 60.1
(CHNH), 62.5 (CH2OH), 64.9 (CH2OSi), 79.5 (OCq),
127.6, 129.6 (CH-Ph), 133.5 (Cq-Ph), 135.5 (CH-Ph),
155.1 (C@O) ppm; MS (DCI, NH3): m/z = 541 (100)
[M+H+]; HRMS (DCI, NH3): calcd for C31H49N2O4Si
[M+H+] 541.3462, found 541.3464.
4.1.11.1. (2S,5R)-2-(Hydroxymethyl)-5-(((S)-1-hydro-
xybutan-2-ylamino)methyl)pyrrolidine (19cis). Compound
18cis (39.4 mg, 73.0 lmol) was treated according to gen-
eral procedure G. The crude product was purified by
column chromatography on silica gel (0.8 g, CH2Cl2/
MeOH/NH4OH 76:20:4) to give 19cis (12.5 mg, 85%):
4.1.10.2. (2S,5S)-tert-Butyl 2-((tert-butyldiphenylsilyl-
oxy)methyl)-5-(((S)-1-hydroxy-butan-2-ylamino)methyl)-
pyrrolidine-1-carboxylate (18trans). Compound 17trans
(18.8 mg, 40.3 lmol) was treated according to general
procedure F. The crude product was purified by flash
column chromatography on silica gel (2 g, EtOAc/
MeOH/NH4OH 98:0:2 then 97:1:2) to give 18trans
colourless oil; Rf = 0,33 (CH2Cl2/MeOH/NH4OH
25
76:20:4); ½aꢁ +7.1 (c 1.3, MeOH); NMR 1H
D
(300 MHz, CD3OD) d = 0.90 (t, 3J = 7.5 Hz, 3H,
CH3), 1.31–1.57 (m, 4H, H-4, H-3, CH3CH2), 1.77–
1.95 (m, 2H, H-40, H-30), 2.43–2.51 (m, 1H, CHNH),
2.62 (AB part of an ABX, 2J = 11.6 Hz, 3J = 7.8 Hz,
3J = 5.0 Hz, da ꢀ db = 46.4 Hz, 2H, CH2NH), 3.38
(14.2 mg, 65%): colourless oil; Rf = 0.46 (EtOAc/
25
D
MeOH/NH4OH 97:1:2); ½aꢁ ꢀ35.3 (c 2.0, CHCl3); IR
(neat) mmax = 3435 (O–H), 3135, 3071, 3049, 2963,
2858 (C–H), 1690 (C@O), 1589, 1473 (C@C), 1113
(C–O) cmꢀ1; NMR 1H (300 MHz, CDCl3) d = (as a
70/30 mixture of rotamers A and B) 0.87–0.94 (m, 3H,
CH3), 1.05 (s, 9H, SiC(CH3)3), 1.29 (s, 6.3H, OC(-
CH3)3A), 1.34–1.50 (m, 2H, CH3CH2), 1.46 (s, 2.7H,
OC(CH3)3B), 1.75–2.17 (m, 4H, 2· H-4, 2· H-3),
2
3
(dd, J = 11.1 Hz, J = 6.7 Hz, 1H, CH2OH), 3.49 (AB
part of an ABX, 2J = 10.9 Hz, 3J = 6.0 Hz, 3J =
5.4 Hz, da ꢀ db = 16.8 Hz, 2H, CH2OH), 3.61 (dd,
3
2J = 11.1 Hz, J = 4.2 Hz, 1H, CH02OH) ppm; NMR
13C (75 MHz, CD3OD) d = 10.8 (CH3), 24.8 (CH3CH2),
28.4 (C-3), 30.4 (C-4), 53.2 (CH2NH), 59.9 (C-5), 61.6
(C-2), 62.4 (CHNH), 63.8 (CH2OH), 66.1 (CH2OH)
ppm; MS (DCI, NH3): m/z = 203 (100) [M+H+]; HRMS
(DCI, NH3): calcd for C10H23N2O2 [M+H+] 203.1760,
found 203.1760.
2
2.32–2.39 (m, 0.3H, CH2NHB), 2.43 (dd, J = 11.4 Hz,
3J = 8.0 Hz, 0.7H, CH2NHA), 2.49–2.58 (m, 1H,
CHNH), 2.94 (dd, 2J = 11.3 Hz, 3J = 2.3 Hz, 0.3H,
CH0 NHB), 3.02 (dd, 2J = 11.4 Hz, 3J = 3.6 Hz, 0.7H,
CH02NHA), 3.26 (dd, 2J = 10.6 Hz, 3J = 6.1 Hz, 1H,
2
CH2OH), 3.46 (dd, 2J = 9.5 Hz, 3J = 7.7 Hz, 0.7H,
CH2OSiA), 3.59 (dd, 2J = 10.6 Hz, 3J = 4.0 Hz, 1H,
CH02OH), 3.68–3.98 (m, 3.3H, H-5, H-2, CH2OSiB,
CH02 OSi), 7.33–7.46 (m, 6H, H-Ph), 7.60–7.67 (m,
4H, H-Ph) ppm; NMR 13C (75 MHz, CDCl3) d = (as
a mixture of rotamers A and B) 10.4 (CH3B), 10.5
(CH3A), 19.2 (SiCqA), 19.3 (SiCqB), 24.4 (CH3CH2B),
24.7 (CH3CH2A), 25.9 (C-4B or C-3B), 26.2 (C-4A
or C-3A), 26.8 (SiC(CH3)3), 27.8 (C-4 or C-3), 28.3
(OC(CH3)3A), 28.6 (OC(CH3)3B), 49.3 (CH2NHB),
49.4 (CH2NHA), 58.4 (C-5A), 58.5 (C-5B), 58.7 (C-2B),
58.8 (C-2A), 60.2 (CHNHA), 60.5 (CHNHB), 62.3
4.1.11.2. (2S,5S)-2-(hydroxymethyl)-5-(((S)-1-hydro-
xybutan-2-ylamino)methyl)pyrrolidine (19trans). Com-
pound 18trans (33.6 mg, 62.2 lmol) was treated
according to general procedure G. The crude product
was purified by column chromatography on silica gel
(0.8 g, CH2Cl2/MeOH/ NH4OH 74:20:6) to give 19trans
(10.8 mg, 86%): colourless oil; Rf = 0.29 (CH2Cl2/
25
D
MeOH/NH4OH 74:20:6); ½aꢁ +22.7 (c 1.1, MeOH);
1
3
NMR H (300 MHz, CD3OD) d = 0.92 (t, J = 7.5 Hz,
3H, CH3), 1.33–1.56 (m, 4H, H-4, H-3, CH3CH2),
1.84–2.03 (m, 2H, H-40, H-30), 2.45–2.53 (m, 1H,

V. Faugeroux et al. / Bioorg. Med. Chem. 15 (2007) 5866–5876
5875
3
CHNH), 2.60 (d, J = 6.5 Hz, 2H, CH2NH), 3.19–3.30
(m, 2H, H-5, H-2), 3.46 (d, J = 5.9 Hz, 2H, CH2OH),
4.2. Biological tests
3
3.48 (AB part of an ABX, 2J = 11.1 Hz, 3J = 6.7 Hz,
3J = 4.4 Hz, da ꢀ db = 51.8 Hz, 2H, CH2OH) ppm;
NMR 13C (75 MHz, CD3OD) d = 10.8 (CH3), 24.8
(CH3CH2), 28.7 (C-3), 30.7 (C-4), 52.6 (CH2NH), 58.6
(C-5), 60.4 (C-2), 62.1 (CHNH), 64.0 (CH2OH), 65.5
(CH2OH) ppm; MS (DCI, NH3): m/z = 203 (100)
[M+H+]; HRMS (DCI, NH3): calcd for C10H23N2O2
[M+H+] 203.1760, found 203.1759.
Susceptibility of M. tuberculosis H37Rv to compounds
19cis, 19trans and 24 was tested by determining the min-
imum inhibitory concentration (MIC). We used a color-
imetric microassay based on the reduction of MTT
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-
mide, Sigma) to formazan by metabolically active
cells.25 Briefly, serial twofold dilutions of each drug were
prepared in 7H9 broth (Middlebrook 7H9 broth base
(Difco)) using 96-well microtitre plates and 100 ll of
M. tuberculosis H37Rv suspension in 7H9 broth was
added to each well. After 6 days incubation, MTT was
added (50 ll, 1 mg/ml). After one day incubation, solu-
bilisation buffer was added to each well. The optical
densities were measured at 570 nm. The MIC was deter-
mined as the lowest concentration of drug that inhibited
bacterial growth (absorbance from untreated bacilli was
taken as a control for growth).
0
0
´
4.1.12. (5S,5 S)-5,5 -Bis((tert-butyldiphenylsilyloxy)eme-
thyl)-2,20-bipyrrolidine (23). To the purified mixture of
imines 13a/13b (221 mg, 656 lmol) in anhydrous and de-
gassed DME (0.6 mL) under argon was added Ti(Oi-
Pr)4 (196 lL, 656 lmol). After 5 min, Sm(0) (109 mg,
727 lmol) and I2 (100 lL of a 1 M solution in degassed
DME, 0.1 mmol) were successively added. The reaction
mixture was stirred for 2 h at room temperature before
being diluted with CH2Cl2 and quenched by addition
of
a 15% aqueous NaOH saturated with NaCl
(4.0 mL). The organic layer was separated, the aqueous
phase treated again with a 15% aqueous NaOH satu-
rated with NaCl (2.0 mL) and extracted with CH2Cl2.
The combined organic phases were then filtered through
Celite. The filtrate was washed with brine, dried over
Na2SO4, filtered and concentrated under reduced pres-
sure. The crude product was purified by column chro-
matography on silica gel (22 g, CH2Cl2/MeOH/
References and notes
1. World Health Organisation Tuberculosis Fact Sheet Nꢁ
104, 2006. See: http://www.who.int/mediacentre/fact-
sheets/fs104/en.
2. (a) Wilkinson, R. G.; Sheperd, R. G.; Thomas, J. P.;
Baughn, C. J. Am. Chem. Soc. 1961, 83, 2212; (b) Sheperd,
R. G.; Baughn, C.; Cantrall, M. L.; Goodstein, B.;
Thomas, J. P.; Wilkinson, R. G. Ann. N.Y. Acad. Sci.
1966, 135, 686.
NH4OH 98.3:0.5:1.2) to give 23 (45.2 mg, 20%) and 9
25
D
(65.8 mg, 30%). Compound 23: yellow oil; ½aꢁ ꢀ3.0 (c
ˇ
´
3. (a) Lee, R. E.; Mikusova, K.; Brennan, P. J.; Besra, G. S.
J. Am. Chem. Soc. 1995, 117, 11829; (b) Khoo, K.-H.;
Douglas, E.; Azadi, P.; Inamine, J. M.; Besra, G. S.;
1
1.9, CHCl3); NMR H (300 MHz, CDCl3) d = 1.06 (s,
9H, SiC(CH3)3), 1.33–1.42 (m, 2H, 2· H-3), 1.43–1.52
(m, 2H, 2· H-4), 1.78–1.88 (m, 4H, 2· H-30, 2· H-40),
1.92–2.15 (m, 2H, 2· NH), 2.91–3.02 (m, 1H, 2· H-2),
3.31–3.36 (m, 2H, 2· H-5), 3.56 (d, 3J = 5.8 Hz, 4H,
2· CH2OSi), 7.35 (m, 6H, H-Ph), 7.64–7.68 (m, 4H,
H-Ph) ppm; NMR 13C (75 MHz, CDCl3) d = 19.3
(SiCq), 26.9 (SiC(CH3)3), 27.8 (C-4), 29.1 (C-3), 59.2
(C-5), 62.6 (C-2), 66.6 (CH2OSi), 127.6, 129.6 (CH-
Ph), 133.6, 133.6 (Cq-Ph), 135.6, 135.6 (CH-Ph) ppm;
MS (DCI, NH3): m/z = 677 (100) [M+H+]; HRMS
(DCI, NH3): calcd for C42H57N2O2Si2 [M+H+]
677.3959, found 677.3958.
ˇ
Mikusova, K.; Brennan, P. J.; Chatterjee, D. J. Biol.
Chem. 1996, 271, 28682.
´
4. (a) Cole, A.; May, P. M.; Williams, D. R. Agents Actions
1981, 11, 296; (b) Solecki, T. J.; Aviv, A.; Bogden, J. D.
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¨
6. Reynolds, R. C.; Bansal, N.; Rose, J.; Friedrich, J.; Suling,
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7. Garcıa-Garcıa, A.; Galvez, J.; De Julian-Ortiz, J.; Garcıa-
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´
´
´
´
´
J. Biomol. Screen. 2005, 10, 206.
4.1.13. (5S,50S)-5,50-Bis(hydroxymethyl)-2,20-bipyrroli-
dine (24). Compound 23 (49.5 mg, 73.2 lmol) was trea-
ted according to general procedure G with a 2 M
methanolic HCl. The crude product was purified by
column chromatography on silica gel (2 g, CH2Cl2/
MeOH/NH4OH 74:20:6) to give 24 (9.7 mg, 66%): yel-
8. Lee, R. E.; Protopopova, M.; Crooks, E.; Slayden, R. A.;
Terrot, M.; Barry, C. E., III J. Comb. Chem. 2003, 5, 172.
9. (a) Jia, L.; Tomaszewski, J. E.; Hanrahan, C.; Coward, L.;
Noker, P.; Gorman, G.; Nikonenko, B.; Protopopova, M.
Br. J. Pharmacol. 2005, 144, 80; (b) Jia, L.; Tomaszewski,
J. E.; Noker, P. E.; Gorman, G. S.; Glaze, E.; Protopop-
ova, M. J. Pharm. Biomed. Anal. 2005, 37, 793.
low oil; Rf = 0.26 (CH2Cl2/MeOH/NH4OH 74:20:6);
10. Bogatcheva, E.; Hanrahan, C.; Nikonenko, B.; Samala,
R.; Chen, P.; Gearhart, J.; Barbosa, F.; Einck, L.; Nacy,
C. A.; Protopopova, M. J. Med. Chem. 2006, 49, 3045.
11. Razafimahfa, D.; Ralambomanana, D. A.; Hammouche,
25
D
½aꢁ +21.7 (c 0.7, MeOH); NMR 1H (300 MHz,
CD3OD) d = 1.36–1.54 (m, 4H, 2· H-3, 2· H-4),
1.85–1.99 (m, 4H, 2· H-30, 2· H-40), 2.98–3.06 (m,
2H, 2· H-2), 3.22–3.30 (m, 2H, 2· H-5), 3.48 (AB part
of an ABX, 2J = 10.9 Hz, 3J = 6.3 Hz, 3J = 5.5 Hz,
da ꢀ db = 12.1 Hz, 4H, 2· CH2OH) ppm; NMR 13C
(75 MHz, CD3OD) d = 28.8 (C-4), 30.2 (C-3), 60.7
(C-5), 63.6 (C-2), 65.3 (CH2OH) ppm; MS (DCI,
NH3): m/z = 201 (100) [M+H+]; HRMS (DCI, NH3):
calcd for C10H21O2N2 [M+H+] 201.1603, found
201.1600.
´
L.; Pelinski, L.; Lauvagie, S.; Bebear, C.; Brocard, J.;
Maugein, J. Bioorg. Med. Chem. Lett. 2005, 15, 2301.
´
12. Marotte, K.; Ayad, T.; Genisson, Y.; Besra, G. S.; Baltas,
M.; Prandi, J. Euro. J. Org. Chem. 2003, 2557.
13. The chiral 2,20-bipyrrolidine scaffold has already been
successfully exploited in asymmetric catalysis and has been
shown to give well-characterized complexes with ZnCl2:
(a) Alexakis, A.; Tomassini, A.; Chouillet, C.; Roland, S.;
Mangeney, P.; Bernardinelli, G. Angew Chem. Int. Ed.

5876
V. Faugeroux et al. / Bioorg. Med. Chem. 15 (2007) 5866–5876
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tetradentate ligands was assessed by simple molecular
mechanics structural optimization (MSI/Insight II/Dis-
cover 3/esff force field). For example, energetically mini-
mized zinc chelates generated from the all-S isomer of the
targeted bipyrrolidine 24 (A) and the parent drug EMB
(B) displayed comparable geometry.
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delivered a 69% yield in coupling product. In our hands
however, the reaction essentially yielded the reduction
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Synth. Commun. 1990, 20, 981.
15. (a) Horenstein, B. A.; Zabinski, R. F.; Schramm, V. L.
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