Synthesis of non glycosidic nucleobase-sugar mimetics

Article abstract of DOI:10.1016/j.crci.2009.11.004

Biologically active organic molecules acting as nucleoside mimics are frequently encountered in pharmaceutical research. They are either synthetic heterocycles, which miss the sugar-derived interactions with the active site of the nucleoside-binding prote

Full text of DOI:10.1016/j.crci.2009.11.004

C. R. Chimie 13 (2010) 1284–1300
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Full paper/Memoire
Synthesis of non glycosidic nucleobase-sugar mimetics
Wilfried Hatton a,c, Daniela Arosio b,c, Marco Re a, Daniele Giudici a,
Anna Bernardi a,c, Pierfausto Seneci a,c,
*
a
`
Universita degli Studi di Milano, Dipartimento di Chimica Organica e Industriale, Via Venezian 21, 20133 Milano, Italy
b C.N.R.-Istituto di Scienze e Tecnologie Molecolari (ISTM), Via Fantoli 16/15, 20138 Milano, Italy
c Centro Interdisciplinare Studi Biomolecolari ed applicazioni Industriali (CISI), Via Fantoli 16/15, 20138 Milano, Italy
A R T I C L E I N F O
A B S T R A C T
Article history:
Biologically active organic molecules acting as nucleoside mimics are frequently
encountered in pharmaceutical research. They are either synthetic heterocycles, which
miss the sugar-derived interactions with the active site of the nucleoside-binding protein,
or natural products containing a glycosidic linkage, which may cause bioavailability and
metabolic stability problems. We report here the concept of synthetic full nucleoside
mimics, including both a N-containing nucleobase-like portion and a sugar-like moiety,
where the latter consists of 5- and 6-membered carbacycles connected by a more stable
and drug-like C–N bond to the nucleobase mimic. Compounds 14, 16 (indolinones), 21 and
23 (benzimidazolones) have been prepared as model compounds.
Received 9 September 2009
Accepted after revision 13 November 2009
Available online 8 February 2010
Keywords:
Epoxide opening
Indolinone
Benzimidazolone
Nucleoside mimic
Heterocycles
Kinases
´
ß 2009 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
ty issues connected to glycosidic linkages and sugars. This
concept is supported by the synthetic indolocarbazole
Mimicry of nucleosides is an active research field,
because of the many potential applications in chemical
biology and drug discovery. Probably the most popular
application consists of ATP-competitive kinase inhibitors
[1]. Naturally occurring ATP-competitive inhibitors are
usually composed of a heterocyclic, nucleobase-like part
connected to a sugar ribose via a glycosidic bond. Apart
from several specificity and toxicity issues, the glycosidic
bond and the carbohydrate moiety often create stability
and bioavailability problems in pharmacologically rele-
vant conditions [2]. Many of the known synthetic ATP-
competitive kinase inhibitors consist of heterocyclic
structures capable of replacing the nucleobase in the
conserved ATP-binding site of the enzymes [3]. The affinity
and possibly the specificity of such molecules could be
improved by sugar-like appendages capable of engaging
the ribose-binding portion of the active site, while being
devoid of the above-mentioned stability and bioavailabili-
SRN-003-556 (1) (compare with the naturally occurring,
glycosidic bond-containing K252a (2), Fig. 1), which is an
in vivo active, potent kinase inhibitor [4].
Here, we report on the general synthetic approaches
capable of affording two classes of molecular structures,
bearing 5- and 6-membered carbocyclic polyols of the
general formula A or B shown in Chart 1. These examples
contain indolinone (Z CH2) or benzimidazolone (Z NH)
rings as the nucleobase decoy. Such heterocycles have
been used previously in the synthesis of ATP-competitive
kinase inhibitors [5] and represent therefore an interesting
model system.
2. Results and discussion
2.1. Epoxide opening
The envisioned modular strategy (Chart 1), allows the
access to chemical diversity via the opening of two
epoxides, enantiomerically pure 3 [6a] and racemic 4
(The epoxide 4 was obtained by epoxidation of trans 4-tert-
butyl-dimethyl-silanyloxy)-cyclopent-2-enol [7] (see the
* Corresponding author.
E-mail address: pierfausto.seneci@unimi.it (P. Seneci).
1631-0748/$ – see front matter ß 2009 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2009.11.004

W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
1285
Fig. 1. Structure of SRN-003-556 (1) and K252a (2).
experimental section) with different anilines. Further N-
functionalization and Pd-catalyzed ring formation yield
the target nucleobase-sugar mimics. Known epoxide 3 was
chosen because it is easily available in enantiopure form
and has been used for the synthesis of sugar mimics [6].
Easily available epoxide 4 was introduced as a closer mimic
of naturally occurring sugars.
The opening of epoxides with anilines in the presence of
Lewis acid promoters is amply documented [8a–g], and a
brief screening was performed to identify the best reaction
conditions for substrates 3 and 4, using aniline 5a or 2-
chloroaniline 5b as nucleophiles (Scheme 1). Results are
detailed in Table 1.
Both regioisomers 7 and 8 (structures assigned by nOe
experiments) were formed with epoxide 4, whereas the C2’
symmetry axis of compound 3 led only to isomer 6.
Somewhat surprisingly, yields for the reaction with
epoxide 3 were consistently higher with 2-chloroaniline
5b than with 5a. Both epoxides 3 and 4 (the latter requiring
stronger reaction conditions) reacted with good yields in
presence of InBr3 [8a] (entries 3, 7, 8, 9, 13, Table 1) or
Yb(OTf)3 [8b], (entries 2, 6, 12, Table 1). Bi-based catalysts
[8c,8d] were less performing under all the examined
reaction conditions (entries 1, 4, 5, 10, 11, Table 1).
Eventually, InBr3 was selected as the catalyst for further
experiments. Although its performance was overall similar
Scheme 1. Opening of epoxides 3 and 4 with anilines 5a,b.
Table 1
Opening of epoxides 3[a] and 4[b] with anilines 5a,b.
EntryEpoxideAnilinePromoterReaction time (h)Compound/yield (%)[c]
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
3
4
5a
5a
5a
5b
5b
5b
5b
Bi(OTf)3 18
Yb(OTf)3 18
6a/55
6a/77
6a/94
6b/47
6b/65
6b/83
6b/85
6b/91
7a/54
8a/22
InBr3
BiCl3
2.5
72
Bi(OTf)3 18
Yb(OTf)3 18
InBr3
2.5
5b[d] InBr3
2.5
8
5a
InBr3
10
11
12
13
4
4
4
4
5a
Bi(OTf)3 48
7a/n.i.[e]
8a/n.i.[e]
5a
5a
5b
BiCl3
48
8
7a/27[f]
8a/23[f]
Yb(OTf)3
InBr3
7a/67[f]
8a/15[f]
8
7b/50
8b/25
[a] Unless otherwise noted, reactions were performed with 0.1 eq.
promoter and 1.1 eq. aniline in DCM at RT.
[b] Reactions were performed with 0.5 eq. promoter and 1.5 eq. aniline in
CH3Cl at reflux.
[c] Isolated yields after chromatography, unless otherwise noted.
[d] 1.5 eq of aniline were used.
[e] Not isolated.
[f] NMR yields estimated from crude reaction mixtures.
to Yb(OTf)3, we were often able with InBr3 to significantly
reduce reaction times (compare entries 2 and 3, Table 1).
Anilines 5c–h were then used with the same experimental
protocols to test the versatility of our strategy (Scheme 2).
Using epoxide 3, yields were good to excellent with
anilines 5c–f (entries 1–4), i.e. comparable to those
obtained with 5a,b. Anilines 5 g and 5 h gave moderate
yields (entries 5–6), probably due to the poor nucleophi-
licity of their nitrogen atom. Epoxide 4 confirmed its
overall lower activity, even under stronger reaction
conditions, and did not react with deactivated anilines
5 g and 5 h (entries 11–12). Yields obtained with anilines
5cf were nevertheless good (entries 7–10). Results are
reported in Table 2.
Chart 1. General structures of the targets and retrosynthetic approaches.

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W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
Table 2
Opening of epoxides 3[a] and 4[b] with anilines 5c-h (Scheme 2).
Entry
Epoxide
Aniline
Reaction
time (h)
Compound/yield
(%)[c]
1
2
3
4
5
6
3
3
3
3
3
3
5c
5d
5e
5f
15
4
6c/82
6d/98
6e/97
6f/80
6g/43
6h/40
15
5
5g
5h
72
48
7
4
4
4
4
4
4
5c
5d
5e
5f
48
24
30
24
X
7c/40
8c/30
8
7d/64
8d/21
9
7e/52
8e/14
10
11
12
7f/58
8f/22
5g
5h
7g/n.i.d
8g/n.i.d
X
7h/n.i.d
8h/n.i.d
Scheme 2. Opening of epoxides 3 and 4 with anilines 5c-h.
[a] Reactions were performed with 0.1 eq. promoter and 1.1 eq. aniline in
2.2. Synthesis of indolinones 14 and 16
DCM at RT.
[b] Reactions were performed with 0.5 eq. promoter and 1.5 eq. aniline in
CH3Cl at reflux.
We then proceeded to the synthesis of indolinones 14
and 16 starting respectively from 6a and a mixture of
compounds 7a and 8a. It must be noted that the formation
of both regioisomers from the opening of epoxide 4
(Scheme 1) is of no relevance from now on, as the two
regioisomers are converted into a single racemate after the
first reaction step (step a, Scheme 3).
[c] Isolated yields, after chromatographic purification.
[d] Not isolated.
were isolated respectively in 47 and 70% unoptimized
yield. With indolinone 11, 30% of starting material was
recovered and could be recycled.
Sequential protection of the free hydroxyl groups (step
a, Scheme 3) and chloroacetylation of the fully O-protected
aniline (step b, Scheme 3) afforded respectively 9 and 10 in
good to excellent yields. Both compounds could be used
without purification in the subsequent cyclization to the
indolinone ring using typical Buchwald’s conditions [9]
(step c, Scheme 3). O-protected indolinones 11 and 12
With protected compounds 11 and 12 in hands, we
decided to perform an aldolisation on the free CH2 position
of the heterocycle in order to obtain 3-alkylidene products,
as similar heterocycles are known to be active on kinases in
the literature [10]. Therefore, we performed an aldol
condensation (step a, Scheme 4) according to established
protocols [10]. 3-(Benzylidenyl)indolin-2-ones 14 and 16
Scheme 3. Synthesis of indolinones 11 and 12.

W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
1287
Scheme 5. Synthesis of ureas 19 and 20.
formation with chlorosulfonylisocyanate (step b, Scheme
5) yielded respectively 19 and 20 in good overall yields. It
has to be noted that O-deprotection occurred during urea
formation from compound 17, while the same Si-protect-
ing group was not removed from compound 18.
Scheme 4. Synthesis of compound 14 and 16.
Cyclization of 19 and 20 was achieved by a slight
modification of a strategy, recently proposed by McLaugh-
lin et al. [11], using Pd(OAc)2 and Buchwald’s X-Phos ligand
(step a, Scheme 6) [12]. Benzimidazolones 21 and 22 were
isolated in good yield and some starting material was
recovered to be recycled. Final O-deprotection of com-
pound 22 (step b, Scheme 6) yielded benzimidazolone 23
in quantitative yield.
were obtained in an overall 85 and 59% yield respectively,
and in a ꢀ 60/40 E/Z ratio, after deprotection (step b,
Scheme 4). Unfortunately, but not unexpectedly [10],
single geometric isomers isolated by chromatography
quickly equilibrated to the original E/Z ratio in solution.
2.3. Synthesis of benzimidazolones 21 and 23
3. Biology
The synthesis of benzimidazolones 21 and 23 (Scheme
6) entailed a key Pd-catalyzed cyclization of intermediate
ureas 19 and 20. Protection of 6b or of a mixture of
compounds 7b and 8b (step a, Scheme 5), followed by urea
We have tested compounds 16, 21 and 23 on a panel of
48 kinases (single point determination, 20
mM) Best
results on selected 12 kinases are reported on Chart 2.
Chart 2. Percentage inhibition of compounds 16, 21 and 23 on kinases.

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W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
piperidine and triethylamine were dried over calcium
hydride; iPrOH and 2,6-lutidine were dried over activated
molecular sieves. Reactions requiring anhydrous condi-
tions were performed under nitrogen or argon. Thin-layer
chromatography (TLC) was carried out with precoated
silica gel plates. Purifications were performed by flash
chromatography carried out with silica gel (230–
400 mesh) or by Biotage SP1TM Purification System. Mass
spectra were obtained with an ESI apparatus Bruker
Esquire 3000 plus. Optical rotations [
in a cell of 1 dm pathlength and 1 mL capacity. 1H and 13
spectra were recorded at 300 K on a 400 MHz spectrome-
ter. Chemical shifts
for 1H and 13C are expressed in ppm
a] were measured
D
C
d
relative to internal Me4Si as standard. Signals were
abbreviated as s: singlet; bs: broad singlet; d: doublet;
t: triplet; q: quartet; sp: septuplet; m: multiplet.
Each molecule was numbered without following the
IUPAC numeration, and the numeration we used is
reported on schemes for all the new compounds synthe-
sized.
5.1. Epoxide opening: general procedure for compound 3
Scheme 6. Synthesis of benzimidazolones 21 and 23.
To a 0.8 M solution of 3[6a] (1 mol equiv.) in CH2Cl2
(technical grade) aniline 5a–h (1.5 mol equiv.) and InBr3
(0.1 mol equiv.) were added. The reaction mixture was
stirred for 2.5 h at room temperature, monitoring the
reaction progression by TLC (6/4 petroleum ether/EtOAc).
After reaction completion the solution was evaporated and
all the compounds were isolated by flash chromatography
In particular, compound 16 shows promising results on
several kinases (TRK-B and VEGF-R2 in particular).
Consequently, we measured the IC50 of compound 16
on several kinases, which obtained a 24
m
M IC50 value
for both TRK-B and VEGF-R2, and a 50
IKK-2.
m
M IC50 value for
or by Biotage SP1TM
.
4. Conclusions
We have devised a practical strategy to tether a 5- and a
6-membered carbocyclic polyol to a heterocyclic structure
with the function of a nucleobase decoy. We have shown
that this strategy could be extended using different
anilines to perform epoxide opening reactions.
The molecules described here, although not yet
structurally optimized, are expected to lead to potent
and selective ATP-competitive kinase inhibitors, since 3-
substituted indolin-2-ones and N-monosubstituted benzi-
midazolones represent a well-established class of tyrosine
kinase inhibitors, which exhibit selectivity toward differ-
ent receptor tyrosine kinases [5].
Indeed, a preliminary set of tests allowed to determine
a medium/micromolar activity on several therapeutically
relevant kinases for compound 16, thus providing proof of
principle for our mimic concept. The synthesis of a larger
set of aryl functionalized indolinones and benzimidazo-
lones bearing variously substituted 5- and 6-membered
carbocyclic sugar mimics is ongoing and their test on a
panel of different kinases and other nucleotide-binding
proteins will be reported in due course.
5.2. (1S,2S,4S,5S)-dimethyl-4-hydroxy-5-
(phenylamino)cyclohexane-1,2-dicarboxylate 6a (Fig. 2. – S1)
Starting from 240 mg (1.14 mmol) of epoxide 3, we
obtained a crude reaction product which was purified by
flash chromatography using petroleum ether/EtOAc (60/
40) to afford 6a as a colorless oil (329 mg, 94%). Rf = 0.2
(DCM/EtOAc 65/35). 1H-NMR (400 MHz, CDCl3): 1.65–1.72
(m, 1 H, 6ax-H); 1.81–1.89 (m, 1 H, 3ax-H); 2.21–2.30 (m, 1
H, 3eq-H); 2.38–2.43 (m, 1 H, 6eq-H); 3.09–3.16 (m, 1 H, 1-
H); 3.25–3.32 (m, 1 H, 2-H); 3.46–3.52 (m, 1 H, 5-H); 3.73
(s, 3 H, 8-H or 8’-H); 3.75 (s, 3 H, 8-H or 8’-H); 3.75–3.81 (m,
1 H, 4-H); 6.73 (d, J11–12 = 7.4 Hz, 2 H, 11-H); 6.78 (t, J12–
13 = 7.4 Hz, 1 H, 13-H); 7.21 (t, J11–12 = J12–13 = 7.4 Hz, 2 H,
12-H). 13C-NMR (100.61 MHz, CDCl3): 28.3 (6-C); 31.1 (3-
C); 39.9 (2-C); 40.3 (1-C); 52.2 (8-C + 8’-C); 54.4 (5-C); 68.6
(4-C); 114.0 (11-C); 118.6 (13-C); 129.5 (12-C); 146.5 (10-
C); 174.1 (7-C or 7’-C); 174.5 (7-C or 7’-C). MS (ESI+): 308.0
5. Experimental section
Solvents were dried by standard procedures. Dichlor-
omethane, toluene, methanol, N,N-diisopropylethylamine,
[M + H+] [
a]D = + 40,0 [c = 0.1, MeOH].

W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
1289
5.5. (1S,2S,4S,5S)-dimethyl-4-(3-fluorophenylamino)-5-
hydroxycyclohexane-1,2-dicarboxylate 6d (Fig. 2. – S4)
5.3. (1S,2S,4S,5S)-dimethyl-4-(2-chlorophenylamino)-5-
hydroxycyclohexane-1,2-dicarboxylate 6b (Fig. 2. – S2)
Starting from 100 mg (0.47 mmol) of epoxide 3, we
obtained a crude reaction product which was purified by
flash chromatography using n-hexane/AcOEt (from 100/0
to 50/50) to afford 6d as a colorless oil (151 mg, 98%).
Rf = 0.3 (Hexane/EtOAc 6/4). 1H-NMR (400 MHz, CDCl3):
1.68 (ddd, Jgem = 13.8 Hz, J = 7.1 Hz, J = 4.3 Hz, 1 H, 3ax-H);
1.86 (ddd, Jgem = 13.7 Hz, J = 7.3 Hz, J = 4.6 Hz, 1 H, 6ax-H);
2.17(ddd, Jgem = 13.7 Hz, J = 8.1 Hz, J = 3.8 Hz, 1 H, 6eq-H);
2.36 (ddd, Jgem = 13.8 Hz, J = 8.1 Hz, J = 3.8 Hz, 1 H, 3eq-H);
2.90 (bs, 1 H, OH); 3.08 (ddd, J = 7.6 Hz, J = 7.3 Hz, J = 4.4 Hz,
1 H, 2-H); 3.26 (ddd, J = 7.4 Hz, J = 7.3 Hz, J = 4.8 Hz, 1 H, 2-
H); 3.95 (dd, J = 10.3 Hz, J = 6.6 Hz, 1 H, 4-H); 3.71 (s, 3 H, 8-
H or 8’-H); 3.74 (s, 3 H, 8-H or 8’-H); 3.78–3.85 (bs, 1 H, 5-
H); 6.36–6.46 (m, 3 H, 11-H + 13-H + 15-H); 7.05–7.12 (m,
1 H, 14-H). 13C-NMR (100.61 MHz, CDCl3): 28.2 (3-C); 31.1
(6-C); 39.7 (1-C); 40.1 (2-C); 52.2 (8-C + 8’-C); 53.8 (4-C);
68.1 (5-C); 100.0 + 104.3 + 109.3 (11-C + 13-C + 15-C);
130.4 (14-C); 148.9 (10-C); 164.2 (d, J = 244 Hz, 12-C);
174.2 (7-C or 7’-C); 174.8 (7-C or 7’-C). MS (ESI+): 326
[M + H]+, 348 [M + Na]+.
Starting from 357Smg (1.67Smmol) of epoxide 3, we
obtained a crude reaction product which was purified by
flash chromatography using n-hexane/EtOAc (60/40) to
afford 6b as a colorless oil (520Smg, 91%). RfS=S0.2 (CHCl3/
EtOAc 9/1). 1H-NMR (400SMHz, CDCl3): 1.68-1.77 (m, 1
H, 3ax-H); 1.80-1.88 (m, 1 H, 6ax-H); 2.29-2.42 (m, 2 H,
3eq-HS+S6eq-H); 3.16-3.20 (m, 1 H, 2-H); 3.30-3.33 (m, 1
H, 1-H); 3.53-3.58 (m, 1 H, 4-H); 3.70 (s, 3 H, 8-H or 8’-
H); 3.75 (s, 3 H, 8-H or 8’-H); 3.77-3.88 (m, 1 H, 5-H);
6.73 (t, JS=S7.6SHz, 1 H, 13-H); 6.88 (d, JS=S8.0SHz, 1 H, 15-
H); 7.18 (t, JS=S7.6SHz, 1 H, 14-H); 7.26-7.31 (m, 1 H, 12-
H). 13C-NMR (100.61SMHz, CDCl3): 28.2 (6-C); 31.1 (3-
C); 40.2 (2-C); 40.6 (1-C); 52.3 (8-CS+S8’-C); 55.5 (5-C);
68.8 (4-C); 112.8 (15-C); 118.8 (13-C); 120.9 (11-C);
127.7 (14-C); 129.8 (12-C); 142.1 (10-C); 173.9 (7-
C
or 7’-C); 174.1 (7-C or 7’-C). MS (ESI+): 705.2
[2MS+SNa]+.
5.4. (1S,2S,4S,5S)-dimethyl-4-(4-bromophenylamino)-5-
hydroxycyclohexane-1,2-dicarboxylate 6c (Fig. 2. – S3)
Starting from 103 mg (0.48 mmol) of epoxide 3, we
obtained a crude reaction product which was purified by
Biotage SP1TM using n-hexane/AcOEt (from 100/0 to 20/
80) to afford 6c as a colorless oil (152 mg, 82%). Rf = 0.3
(Hexane/EtOAc 7/3). 1H-NMR (400 MHz, CDCl3): 1.64
(ddd, Jgem = 13.5 Hz, J = 7.2 Hz, J = 4.3 Hz, 1 H, 3ax-H); 1.81
(ddd, Jgem = 13.8 Hz, J = 7.4 Hz, J = 4.6 Hz, 1 H, 6ax-H); 2.14
(ddd, Jgem = 13.8 Hz, J = 7.8 Hz, J = 3.1 Hz, 1 H, 6eq-H); 2.30
(ddd, Jgem = 13.5 Hz, J = 7.8 Hz, J = 3.9 Hz, 1 H, 3eq-H); 2.83
(bs, 1 H, 4-OH); 2.96–3.10 (m, 1 H, 2-H); 3.18–3.26 (m, 1 H,
1-H); 3.32–3.47 (m, 1 H, 4-H); 3.68 (s, 3 H, 8-H or 8’-H);
3.70 (s, 3 H, 8-H or 8’-H); 3.70–3.83 (bs, 1 H, 5-H); 6.53 (d,
J = 8.9 Hz, 2 H, 10-H); 7.21 (d, J = 8.9 Hz, 2 H, 11-H). 13C-
NMR (100.61 MHz, CDCl3): 28.2 (3-C); 31.2 (6-C); 39.8 (1-
C); 40.2 (2-C); 52.4 (8-C + 8’-C); 53.9 (4-C); 68.3 (5-C);
109.6 (10-C); 115.2 (11-C); 132.2 (12-C); 146.1 (13-C);
174.3 (7-C or 7’-C); 174.8 (7-C or 7’-C). MS (ESI+): 386
[M + H]+.
5.6. (1S,2S,4S,5S)-dimethyl-4-(2,3-dimethylphenylamino)-
5-hydroxycyclohexane-1,2-dicarboxylate 6e (Fig. 2. – S5)
Starting from 107 mg (0.5 mmol) of epoxide 3, we
obtained a crude reaction product which was purified by
flash chromatography using n-hexane/AcOEt (from 100/0
to 60/40) to afford 6e as a brown oil (163 mg, 97%). Rf = 0.25
(Hexane/EtOAc 7/3). 1H-NMR (400 MHz, CDCl3): 1.71 (ddd,
J
J
gem = 13.6 Hz, J = 6.8 Hz, J = 4.3 Hz, 1 H, 3ax-H); 1.88 (ddd,
gem = 13.8 Hz, J = 7.1 Hz, J = 4.6 Hz, 1 H, 6ax-H); 2.05 (s, 3 H,
17-H); 2.13–2.24 (m, 1 H, 6eq-H); 2.28 (s, 3 H, 16-H); 2.38
(ddd, Jgem = 13.6 Hz, J = 8.2 Hz, J = 3.7 Hz, 1 H, 3eq-H); 3.04–
3.13 (m, 1 H, 2-H); 3.23–3.31 (m, 1 H, 1-H); 3.48–3.57 (m, 1
H, 4-H); 3.72 (s, 3 H, 8-H or 8’-H); 3.74 (s, 3 H, 8-H or 8’-H);
3.80–3.85 (bs, 1 H, 5-H); 6.60–6.68 (m, 2 H, 13-H + 15-H);
7.02 (t, J = 7.8 Hz, 1 H, 14-H). 13C-NMR (100.61 MHz,
CDCl3): 12.7 (17-C); 20.8 (16-C); 28.6 (3-C); 31.1 (6-C);
39.7 (1-C); 40.3 (2-C); 52.1 (8-C + 8’-C); 53.8 (4-C); 68.3 (5-

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W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
C); 108.9 (15-C); 120.1 (13-C); 121.2 (11-C); 126.3 (14-C);
136.9 (12-C); 144.7 (10-C); 174.3 (7-C or 7’-C); 174.8 (7-C
or 7’-C). MS (ESI+): 336 [M + H]+, 358 [M + Na]+.
H, 5-H); 4.93 (d, J = 7.5 Hz, 1 H, 9-H); 6.56 (d, J = 9.2 Hz, 2 H,
11-H); 7.94 (d, J = 9.2 Hz,
H, 12-H). 13C-NMR
2
(100.61 MHz, CDCl3): 28.1 (3-C); 31.4 (6-C); 39.9 (1-C);
40.1 (2-C); 52.3 (8-C or 8’-C); 52.4 (8-C or 8’-C); 53.7 (4-C);
68.0 (5-C); 111.6 (11-C); 126.5 (12-C); 138.0 (13-C); 153.0
(9-C); 174.0 (7-C or 7’-C); 174.5 (7-C or 7’-C). MS (ESI+):
353 [M + H]+, 375 [M + Na]+.
5.7. (1S,2S,4S,5S)-dimethyl-4-(3,5-dimethoxyphenylamino)-
5-hydroxycyclohexane-1,2-dicarboxylate 6f (Fig. 2. – S6)
Starting from 120 mg (0.56 mmol) of epoxide 3, we
obtained a crude reaction product which was purified by
Biotage SP1TM using n-hexane/AcOEt (from 100/0 to 20/80)
to afford 6f as a colorless oil (164 mg, 80%). Rf = 0.3
(Hexane/EtOAc 7/3). 1H-NMR (400 MHz, CDCl3): 1.64 (ddd,
Jgem = 12.9 Hz, J = 8.1 Hz, J = 4.4 Hz, 1 H, 3ax-H); 1.81 (ddd,
Jgem = 13.9 Hz, J = 8.1 Hz, J = 4.8 Hz, 1 H, 6ax-H); 2.16 (bs, 1
H, 4-OH); 2.24 (ddd, Jgem = 13.9 Hz, J = 6.8 Hz, J = 3.6 Hz, 1 H,
6eq-H); 2.41 (ddd, Jgem = 13.5 Hz, J = 6.9 Hz, J = 3.6 Hz, 1 H,
3eq-H); 3.01 (dd, J = 11.0 Hz, J = 6.1 Hz, 1 H, 2-H); 3.28 (dd,
J = 11.6 Hz, J = 5.6 Hz, 1 H, 1-H); 3.43 (ddd, J = 7.7 Hz,
J = 7.6 Hz, J = 4.0 Hz, 1 H, 4-H); 3.52 (bs, 1 H, 5-H); 3.72
(s, 3 H, 8-H or 8’-H); 3.75 (s, 3 H, 8-H or 8’-H); 3.76 (s, 6 H,
14-H); 5.89 (d, J = 2.1 Hz, 2 H, 11-H); 5.90–5.93 (m, 1 H, 13-
H). 13C-NMR (100.61 MHz, CDCl3): 28.3 (6-C); 31.1 (3-C);
39.7 (1-C); 40.2 (2-C); 52.2 (8-C + 8’-C); 53.7 (4-C); 55.2
(11-C); 68.1 (5-C); 90.3 (13-C); 92.3 (11-C); 149.0 (10-C);
161.8 (12-C); 174.3 (7-C or 7’-C); 174.9 (7-C or 7’-C). MS
(ESI+): 368 [M + H]+, 390 [M + Na]+.
5.9. (1S,2S,4S,5S)-dimethyl-4-hydroxy-5-(pyridin-3-
ylamino)cyclohexane-1,2-dicarboxylate 6h (Fig. 2. – S8)
Starting from 120 mg (0.56 mmol) of epoxide 3, we
obtained a crude reaction product which was purified with
Biotage SP1TM using CH2Cl2/MeOH (from 90/10 to 80/20)
to afford 6h as a white solid (69 mg, 40%). Rf = 0.1 (DCM/
MeOH 9/1). 1H-NMR (400 MHz, CD3OD): 1.77 (ddd,
Jgem = 13.9 Hz, J = 11.3 Hz, J = 5.2 Hz, 1 H, 3ax-H); 2.34 (dt,
Jgem = J = 13.3 Hz, J = 5.1 Hz, 1 H, 6ax-H); 2.52–2.64 (m, 2 H,
3eq-H + 6eq-H); 3.42–3.50 (m, 1 H, 2-H); 3.50–3.56 (m, 1
H, 1-H); 3.84 (s, 3 H, 8-H or 8’-H); 3.85 (s, 3 H, 8-H or 8’-H);
4.05 (dt, J = 10.9 Hz, J = 4.6 Hz, 1 H, 4-H); 4.42 (ddd,
J = 12.9 Hz, J = 9.6 Hz, J = 3.5 Hz, 1 H, 5-H); 7.66–7.73 (m,
2 H, 13-H + 14-H); 8.06–8.16 (m, 1 H, 12-H); 8.16–8.26 (m,
1 H, 11-H). 13C-NMR (100.61 MHz, CD3OD): 30.6 (6-C);
33.6 (3-C); 41.9 (1-C); 42.1 (2-C); 52.2 (8-C + 8’-C); 69.5 (4-
C); 75.2 (5-C); 128.4 (11-C); 129.0 (13-C or 14-C); 129.4
(13-C or 14-C); 131.5 (12-C); 150.5 (10-C); 174.1 (7-C or 7’-
C); 174.4 (7-C or 7’-C). MS (ESI+): 309 [M + H]+.
5.8. (1S,2S,4S,5S)-dimethyl-4-hydroxy-5-(4-
nitrophenylamino)cyclohexane-1,2-dicarboxylate 6g (Fig. 2.
– S6)
Starting from 98 mg (457 mmol) of epoxide 3, we
obtained a crude reaction product which was purified by
flash chromatography using n-hexane/AcOEt (from 100/0
to 50/50) to afford 6g as a colorless oil (69 mg, 43%). Rf = 0.3
(Hexane/EtOAc 6/4). 1H-NMR (400 MHz, CDCl3): 1.65 (ddd,
Jgem = 12.6 Hz, J = 7.7 Hz, J = 4.4 Hz, 1 H, 3ax-H); 1.77 (ddd,
Jgem = 12.9 Hz, J = 7.6 Hz, J = 4.7 Hz, 1 H, 6ax-H); 2.13 (ddd,
Jgem = 12.9 Hz, J = 6.9 Hz, J = 3.0 Hz, 1 H, 6eq-H); 2.31 (ddd,
Jgem = 12.6 Hz, J = 7.7 Hz, J = 4.1 Hz, 1 H, 3eq-H); 2.78 (bs, 1
H, OH); 3.05 (dd, J = 11.0 Hz, J = 6.8 Hz, 1 H, 2-H); 3.22 (dd,
J = 11.4 Hz, J = 6.5 Hz, 1 H, 2-H); 3.54 (dt, J = 11.1 Hz,
J = 7.2 Hz, 1 H, 4-H); 3.63 (s, 3 H, 8-H or 8’-H); 3.68 (s, 3
H, 8-H or 8’-H); 3.80 (ddd, J = 7.3 Hz, J = 7.1 Hz, J = 3.3 Hz, 1
5.10. (1S,2S,4S,5S)-dimethyl-4-(tert-butyldimethylsilyloxy)-
5-(2-chloro-N-phenylacetamido)cyclohexane-1,2-
dicarboxylate 9 (Fig. 2. – S9)
To a solution of compound 6a (273 mg, 0.89 mmol) and
dry 2,6-lutidine (190 mg, 1.78 mmol) in dry CH2Cl2
(4.4 mL), at 0 8C and under N2, TBDMSOTf (398 mg,
1.51 mmol) was added. The reaction was stirred at room
temperature for 2.5 h and monitored by TLC (9/1 CH2Cl2/
EtOAc). After reaction completion, the solvent was
evaporated under reduced pressure and the crude was
taken up with Et2O, washed with H2O and dried with

W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
1291
Na2SO4. The solvent was evaporated under reduced
pressure and the resulting crude silylether intermediate
(345 mg, 92%) was used for the following reaction without
any further purification. Rf = 0.1 (DCM/EtOAc 9/1). MS
(ESI+): 422.2 [M + H+].
173.5 (7-C or 7’-C); 175.2 (7-C or 7’-C). MS (ESI+): 462.0
[M + H+]. [
]D = + 175.0 [c = 1.5, MeOH].
a
To a solution of the silylether intermediate (390 mg,
0.93 mmol) and dry 2,6-lutidine (222 mg, 1.87 mmol) in dry
toluene (2 mL), chloroacetylchloride (181 mg, 1.6 mmol)
was added under nitrogen and at room temperature. The
reactionwasstirredwhilemonitoringbyTLC(8/2petroleum
ether/EtOAc), then the solution was diluted with Et2O and
the organic phase was washed with water. The solvent was
dried with Na2SO4 and evaporated under reduced pressure,
to yield a crude that was purified by flash chromatography
(95/5 CH2Cl2/AcOEt), affording compound 9 (452 mg, 98%).
Rf = 0.4 (Hexane/EtOAc 8/2). 1H-NMR (400 MHz, CDCl3):
0.16 (s, 3 H, 9-H); 0.18 (s, 3 H, 9-H); 0.95 (s, 9H, 11-H); 1.61
(m, 1 H, 6ax-H); 2.25–2.38 (m, 3 H, 3eq-H + 3ax-H + 6eq-H);
3.05–3.11 (m, 1 H, 2-H); 3.20–3.26 (m, 1 H, 1-H); 3.65 (s 3 H,
8-H or 80-H); 3.72 (s, 3 H, 8-H or 80-H); 3.75 (m, 3 H, 4-
H + 2 ꢁ 17-H.); 4.41–4.51 (m, 1 H, 5-H); 7.27–7.38 (m, 2 H,
Ar-H); 7,40–7.50 (m, 3 H, Ar-H). 13C-NMR (100.61 MHz,
CDCl3): ꢂ4.3(9-C); ꢂ4.2 (9-C);18.0 (10-C); 25.9(11-C); 26.4
(3-C); 33.5 (6-C); 40.6 (1-C + 2-C); 43.3 (17-C); 52.2 (8-C or
80-C); 64.1 (4-C); 128.8 (Ar-C); 129.9 (Ar-C); 141.4 (12-C);
165.8 (16-C); 173.4(7-C or 70-C); 173.7 (7-C or 70-C). MS
5.12. (1S,2S,4S,5S)-dimethyl-4-(tert-butyldimethylsilyloxy)-
5-((E and Z)-3-(4-isopropylbenzylidene)-2-oxoindolin-1-
yl)cyclohexane-1,2-dicarboxylate 13
To
methanol (290
room temperature, 4-isopropyl-benzaldehyde (27
0.175 mmol) and piperidine (6 L, 0.06 mmol) were added.
a
solution of 11 (67 mg, 0.164 mmol) in dry
L), under nitrogen atmosphere and at
L,
m
m
m
The reaction mixture was stirred ad 65 8C monitoring the
reaction progression by TLC (85/15 petroleum ether/
EtOAc). After reaction completion, the solvent was
evaporated under reduced pressure and the silylether 13
was isolated by flash chromatography (85/15 petroleum
ether/EtOAc) as a E/Z isomeric mixture (251 mg, 94%).
(ESI+): 498.2 [M+H+]. [
a]D = ꢂ174.0 [MeOH, c = 1.0].
5.11. (1S,2S,4S,5S)-dimethyl-4-(tert-butyldimethylsilyloxy)-
5-(2-oxoindolin-1-yl)cyclohexane-1,2-dicarboxylate 11 (Fig.
2. – S10)
In a Schlenk reactor, under argon atmosphere and at
room temperature, 9 (109 mg, 0.22 mmol), Pd(OAc)2 (5 mg,
0.022 mmol) and di-tert-butyl-diphenyl-phosphine (14 mg,
0.48 mmol) were dissolved in dry toluene (240
mL), and dry
DIPEA (63 L, 0.36 mmol) was added. The reaction mixture
m
was stirred at 100 8C for ca. 6 h, monitoring by TLC (95/5
CH2Cl2/AcOH). After reaction completion, the reaction
mixture was taken up with EtOAc (2 mL), filtered on a
pad of celite, and the organic phase was evaporated under
reduced pressure. The crude was purified by flash chroma-
tography (95/5 CH2Cl2/AcOH) affording compound 11
(48 mg, 47%). Starting material 9 (33 mg, 68% conversion)
was also recovered, and could be recycled. Rf = 0.4 (Hexane/
EtOAc 8/2). 1H-NMR (400 MHz, CDCl3): ꢂ0.30 (s, 3 H, 9-H);
ꢂ0.01 (s, 3 H, 9-H); 0.66 (s, 9H, 11-H); 1.65 (dt, Jgem = J1–
5.12.1. Z isomer (Fig. 2. – S11)
Rf = 0.34 (Hexane/EtOAc 9/1). 1H-NMR (400 MHz,
CDCl3): ꢂ0.33 (s, 3 H, 9-H); ꢂ0.03 (s, 3 H, 9-H); 0.66 (s, 9
H, 11-H); 1.30 (d, J25–26 = 7.2 Hz, 6 H, 26-H); 1.60–1.72 (m, 1
H, 3ax-H); 2.20–2.30 (m, 1 H, 6eq-H); 2.42–2.51 (m, 1 H,
3eq-H); 2.79–2.90 (m, 1 H, 6ax-H); 2.92–3.01 (sp, J25–
26 = 7.2 Hz, 1 H, 25-H); 3.37–3.45 (m, 2 H, 1-H + 2-H); 3.82 (s,
3 H, 8-Hor 8’-H);3.84(s, 3 H, 8-H or 8’-H);4.08–4.02(m, 1 H,
5-H);4.53–4.60(m, 1H, 4-H);6.92(d, J15–16 = 8.0 Hz, 1H,16-
H); 7.01 (dt, J = 7.6 Hz, J = 0.9 Hz, 1 H, 14-H); 7.24 (dt,
J = 7.8 Hz, J = 1.2 Hz, 1 H, 15-H); 7.32 (d, J22–23 = 8.0 Hz, 2 H,
23-H); 7.50 (s, 1 H, 20-H); 8.22 (d, J22–23 = 8.0 Hz, 2 H, 22-H).
MS (ESI+): 592 [M + H+].
6ax = 15.6 Hz, J5–6ax = 4.8 Hz,
1 H, 6ax-H); 2.21 (td,
Jgem = 12.0 Hz, J2–3eq = J3eq–4 = 2.0 Hz, 1 H, 3eq-H); 2.44 (td,
Jgem = 15.6 Hz, J1–6eq = J5–6eq = 2.0 Hz, 1 H, 6eq-H); 2.72 (dt,
Jgem = J3ax–2 = 13.5 Hz, J3ax–4 = 4.6 Hz, 1 H, 3ax-H); 3.40 (bs, 2
H, 1-H + 2-H); 3.46 (s, 2 H, 18-H); 3.82 (s 3 H, 8-H or 8’-H);
3.83 (s, 3 H, 8-H or 8’-H); 3.98–4.07 (m, 1 H, 5-H); 4.54 (dt,
J = 11.0 Hz, J3ax–4 = 4.6 Hz, 1 H, 4-H); 6.93 (d, J15–16 = 7.8 Hz, 1
H, 16-H); 7.00 (t, J13–14 = J14–15 = 7.8 Hz, 1 H, 14-H); 7.22 (t,
J14–15 = J15–16 = 7.8 Hz, 1 H, 15-H); 7.18–7.28 (m, 1 H, 13-H).
13C-NMR (100.61 MHz, CDCl3): ꢂ5.5(9-C); ꢂ4.7 (9-C); 17.5
(10-C); 25.3(3-C); 25.4 (11-C); 33.6 (6-C); 36.3 (18-C); 41.0
(2-C); 41.2 (1-C); 52.3 (8-C or 8’-C); 52.4 (8-C or 8’-C); 55.5
(5-C); 66.3 (4-C); 109.2 (16-C); 121.7 (14-C); 124.2 (15-C);
124.4 (17-C); 127.6 (13-C); 145.2 (12-C); 173.4 (19-C);

1292
W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
5.12.2. E isomer (Fig. 2. – S12)
5.14. (1S,2S,4S,5S)-dimethyl-4-(tert-butyldimethylsilyloxy)-
5-(2-chlorophenylamino)cyclohexane-1,2-dicarboxylate 17
(Fig. 2. – S14)
Rf = 0.34 (Hexane/EtOAc 9/1). 1H-NMR (400 MHz,
CDCl3): ꢂ0.28 (s, 3 H, 3-H); 0.06 (s, 3 H, 9-H); 0.66 (s, 9
H, 11-H); 1.32 (d, J25–26 = 6.8 Hz, 6 H, 26-H); 1.58–1.71 (m,
1 H, 3ax-H); 2.21–2.30 (m, 1 H, 6eq-H); 2.44–2.51 (m, 1 H,
3eq-H); 2.79–2.89 (m, 1 H, 6’-H); 2.98 (sp, J25–26 = 6.8 Hz, 1
H, 25-H); 3.40 (bs, 1 H, 2-H); 3.44 (bs, 1 H, 1-H); 3.83 (s, 3 H,
8-H or 8’-H); 3.85 (s, 3 H, 8-H or 8’-H); 3.97–4.06 (m, 1 H, 5-
H); 4.51–4.62 (m, 1 H, 4-H); 6.84–6.89 (m, 1 H, 14-H);
6.92–6.97 (m, 1 H, 16-H); 7.21–7.28 (m, 1 H, 15-H); 7.34 (d,
J22–23 = 8.0 Hz, 2 H, 23-H); 7.60 (d, J22–23 = 8.0 Hz, 2 H, 22-
H); 7.72 (d, J13–14 = 7.2 Hz, 1 H, 13-H); 7.75 (s, 1 H, 20-H).
MS (ESI+): 592 [M + H+].
To a solution of compound 6b (205 mg, 0.6 mmol) and
2,6-lutidine (140
0 8C and under N2, TBDMSOTf (330
m
L, 1.2 mmol) in dry CH2Cl2 (2.4 mL), at
L, 1.44 mmol) was
m
added. The reaction mixture was stirred at room tempera-
ture for 2.5 h, monitoring the reaction progression by TLC
(9/1 CH2Cl2/EtOAc). After reaction completion, the solvent
was evaporated under reduced pressure, the crude was
taken up with Et2O, washed with H2O and dried with
Na2SO4. The solvent was evaporated under reduced
pressure. The crude was purified by flash chromatography
on silica gel (9/1 petroleum ether/EtOAc), affording 17
(232 mg, 85%) that was used as such. A sample of the
silylether was further purified by flash chromatography
(94/6 petroluem ether/EtOAc) for analytical characteriza-
tion. Rf = 0.2 (Hexane/EtOAc 6/4). 1H-NMR (400 MHz,
CDCl3): 0.00 (s, 6 H, 16-H); 0.80 (s, 9 H, 18-H); 1.70–
1.85 (m, 3 H, 3ax-H + 6eq-H + 6ax-H); 2.10 (m, 1 H, 3eq-H);
2.82–2.89 (m, 1 H, 2-H); 3.02–3.09 (m, 1 H, 1-H); 3.36–3.42
(m, 1 H, 4-H); 3.60 (s, 6 H, 8-H and 8’-H); 3.82–3.89 (m, 1 H,
5-H); 6.60 (t, J12–13 = J13–14 = 8.0 Hz, 1 H, 13-H); 6.68 (d, J14–
15 = 8.0 Hz, 1 H, 15-H); 7.05 (t, J13–14 = J14–15 = 8.0 Hz, 1 H,
14-H); 7.20 (m, 1 H, 12-H). 13C-NMR (100.61 MHz, CDCl3):
ꢂ4.7 (16-C); ꢂ4.6 (16-C); 17.9 (17-C); 25.8 (18-C); 27.7 (6-
C); 31.5 (3-C); 39.0 (2-C); 39.6 (1-C); 52.1 (8-C + 8’-C); 53.0
(5-C); 67.8 (4-C); 112.5 (15-C); 119.0 (13-C); 127.9 (14-C);
129.5 (12-C); 142.1 (10-C); 173.9 (7-C or 7’-C); 174.1 (7-C
or 7’-C).
5.13. (1S,2S,4S,5S)-dimethyl-4-hydroxy-5-(3-(4-
isopropylbenzylidene)-2-oxoindolin-1-yl)cyclohexane-1,2-
dicarboxylate 14 (Fig. 2. – S13)
A 1 M solution of TBAF in THF (100
mL, 0.84 mmol) was
added to intermediate silylether 13 (14.5 mg, 0.21 mmol).
The reaction mixture was stirred at room temperature for
16 h, monitoring the reaction progression by TLC (85/15
CH2Cl2/EtOAc). After reaction completion the mixture was
taken up with Et2O and washed with saturated NH4Cl. The
organic phase, dried with Na2SO4, was evaporated under
reduced pressure and the crude product was purified by
flash chromatography (85/15 CH2Cl2/EtOAc) affording
compound 14 (10.5 mg, 90%) as a ꢀ 40/60 (Z/E) isomeric
mixture of Z and E isomers which reequilibrated after any
purification attempt. Rf = 0.2 + 0.4 (DCM/EtOAc 85/15). 1H-
NMR (400 MHz, CDCl3): 1.33 (d, J22–23 = 6.8 Hz, 6 H, 23-H);
1.62–1.78 (m, 1 H, 3eq-H); 2.15–2.40 (m, 2 H, 6ax-H + 6eq-
H); 2.58–2.66 (m, 1 H, 3ax-H); 3.32 (bs, 1 H, 1-H); 3.36 (bs,
1 H, 2-H); 3.82 (s, 3 H, 8-H or 8’-H); 3.84 (s, 3 H, 8-H or 8’-
H); 3.95–4.01 (m, 1 H, 5-H); 4.70–4.86 (m, 1 H, 4-H); 6.43–
6.49 (m, Ar-H, Z isomer); 6.67–6.74 (m, Ar-H, Z isomer);
6.77–6.90 (m, Ar-H, E and Z isomers); 6.95–7.15 (m, Ar-H, E
and Z isomers); 7.19–7.28 (m, Ar-H, E and Z isomers); 7.31
(m, Ar-H, Z isomer); 7.46 (m, Ar-H, Z isomer); 7.52 (m, Ar-
H, E isomer); 7.67 (m, Ar-H, E isomer); 7.70 (m, Ar-H, E
isomer); 8.10 (m, Ar-H, Z isomer). MS (ESI+): 478.0
[M + H+].
5.15. (1S,2S,4S,5S)-dimethyl-4-(1-(2-chlorophenyl)ureido)-
5-hydroxy-cyclohexane-1,2-dicarboxylate 18 (Fig. 2. – S15)
A
solution of chlorosulfonyl isocyanate (70
mL,
0.81 mmol) in dry THF (560 L), under N2, was cooled to
m
ꢂ10 8C and added dropwise over 30 minutes (using a
syringe pump) to a solution of the 17 (232 mg, 0.51 mmol)
in dry THF (1.2 mL). After 20 minutes a second portion of
chlorosulfonyl isocyanate (30
mL, 0.34 mmol) was added
dropwise. The reaction progression was monitored by TLC
(95/5 CH2Cl2/MeOH). After reaction completion, water
(120 mL) was added, and the mixture stirred for 30 minutes
at room temperature. The solution was treated with 3 M
NaOH until pH 8–9, and the organic phase washed twice
with brine and dried with Na2SO4. The solvent was
evaporated under reduced pressure and the crude was
purified by flash chromatography on silica gel (93/7
CH2Cl2/MeOH), affording 18 (158 mg, 81%). Rf = 0.3
(DCM/MeOH 9/1). 1H-NMR (400 MHz, CDCl3): 1.23 (td,
Jgem = J5–6ax = 13.0 Hz, J1–6ax = 4.0 Hz, 1 H, 6ax-H); 1.77 (td,
Jgem = J3ax–4 = 13.6 Hz, J2–3ax = 5.6 Hz, 1 H, 3ax-H); 2.38–

W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
1293
2.52 (m, 2 H, 3eq-H + 6eq-H); 3.12 (bs, 1 H, 1-H); 3.27 (bs, 1
5.17. (ꢃ)-(1S,2S,4R,5S)-4-(tert-butyldimethylsilyloxy)-6-
oxabicyclo[3.1.0]hexan-2-ol 4 (Fig. 2. – S17)
H, 2-H); 3.70–3.55 (m, 4H, 4-H + 8-H or 8’-H); 3.77 (s, 3 H,
8-H or 8’-H); 4.43–4.52 (m, 1 H, 5-H); 7.38 (m, 2 H, 13-
H + 15-H); 7.46 (m, 1 H, 14-H); 7.55 (m, 1 H, 12-H). 13C-
NMR (100.61 MHz, CDCl3): 26.5 (6-C); 33.20 (3-C); 40.5 (2-
C); 40.7 (1-C); 52.1 (8-C or 8’-C); 52.5 (8-C or 8’-C); 58.4 (5-
C); 70.0 (4-C); 128.6 (15-C); 130.4 (13-C); 131.1 (12-C);
132.3 (14-C); 135.3 (11-C); 135.7 (10-C); 159.3 (9-C);
173.3 (7-C or 7’-C); 173.6 (7-C or 7’-C). MS (ESI+): 791.2
To a stirred solution of commercially available (ꢃ)-
(1S,4R)-4-(tert-butyldimethylsilyloxy)cyclopent-2-enol
(3.5 g, 16.33 mmol) in CH2Cl2 (40 mL) 3-chloroperbenzoic
acid (5.63 g, 32.7 mmol) was added and the reaction was
stirred for 3 h at room temperature. The reaction mixture was
diluted with CH2Cl2 (40 mL) and quenched by saturated
Na2CO3. The organic layer was washed (2 ꢁ 60 mL) with
saturated Na2CO3, then with brine (2 ꢁ 60 mL), was dried on
Na2SO4, filtered and concentrated under reduced pressure.
The crude product was purified on silica gel (n-hexane/EtOAc
from 20/80 to 50/50) to afford epoxide 4 (3.21 g, 85%) as a
white solid. Rf = 0.5 (Hexane/EtOAc 6/4). 1H-NMR (400 MHz,
CDCl3): 0.08 (s, 3 H, 3 ꢁ 6-H); 0.10 (s, 3 H, 3 ꢁ 6-H); 0.91 (s, 9
H, 9 ꢁ 8-H); 1.30 (dt, Jgem = 12.6 Hz, J1–5a = J4–5a = 8.4 Hz, 1 H,
5a-H); 2.19 (dt, Jgem = 12.6 Hz, J1–5b = J4–5b = 7.6 Hz, 1 H, 5b-
H); 3.44 (dd, J1–2 = 1.4 Hz, J2–3 = 2.9 Hz, 1 H, 2-H); 3.48 (dd, J3–
4 = 1.4 Hz, J2–3 = 2.9 Hz, 1 H, 3-H); 4.02–4.08 (m, 1 H, 4-H);
4.10–4.16 (m, 1 H, 1-H). 13C-NMR (100.61 MHz, CDCl3): ꢂ4.8
(6-C); ꢂ4.7 (6-C); 18.0 (7-C); 25.7 (8-C); 34.4 (5-C); 57.3 (3-
C); 58.3 (2-C); 69.9 (4-C); 70.6 (1-C). MS (ESI+): 253
[M + Na]+; 231 [M + H]+.
[2M + Na+].
17H21N2O6ClNa: calcd. 407.09804; found 407.09781.
[
a
]D = ꢂ26.7
[c = 1.0,
CHCl3].
HRMS:
C
5.16. (1S,2S,4S,5S)-dimethyl-4-hydroxy-5-(2-oxo-2,3-
dihydro-1H-benzo[d]imidazol-1-yl)cyclohexane-1,2-
dicarboxylate 21 (Fig. 2. – S16)
A solution of 18 (157.9 mg, 0.41 mmol) and iPr2EtN
(215 mL, 1.23 mmol) in dry iPrOH (1.8 mL) (dried on
5.18. Epoxide opening: general procedure for compound 4
molecular sieves and purged with N2) was stirred under N2
atmosphere. The reaction mixture was purged with N2 for
15 minutes and then a first aliquot of X-Phos [9] (2-
dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl)
(24.4 mg, 0.06 mmol) and Pd(OAc)2 (4.6 mg, 0.02 mmol)
were added. The reaction mixture was purged with N2 for
further 15 minutes and the solution was heated to 83 8C.
After 4 h a second aliquot of X-Phos (24.4 mg, 0.06 mmol)
To a 0.061 M solution of 4 [14] (1 mol equiv.) in CHCl3
anilines 5a–h (1.5 mol equiv.) and InBr3 (0.5 mol equiv.)
were added. The reaction mixture was stirred between
10 h to 48 h at reflux, monitoring the reaction progression
by TLC (6/4 petroleum ether/EtOAc). After reaction
completion the solution was evaporated and all the
compounds were isolated by flash chromatography or
with Biotage SP1TM
.
and Pd(OAc)2 (4.6 mg, 0.02 mmol) in iPrOH (300
mL) was
added. The reaction was stirred at 83 8C for 24 h,
monitoring its progression by TLC (EtOAc). The solvent
was evaporated under reduced pressure, the residue taken
up with CH2Cl2, washed once with H2O and dried with
Na2SO4. The crude was purified by flash chromatography
on silica gel (EtOAc), affording 21 (74 mg, 51%) and
recovered starting material 18 (34 mg, 65% conversion).
Rf = 0.2 (DCM/MeOH 9/1). 1H-NMR (400 MHz, CDCl3): 1.78
(td, Jgem = J3ax–4 = 13.2 Hz, J2–6ax = 5.0 Hz, 1 H, 3ax-H); 2.41
(m, 2 H, 6eq-H + 6ax-H); 2.62 (dt, Jgem = 13.7 Hz, J3eq–4 = J2–
3eq = 2.0 Hz, 1 H, 3eq-H); 3.40 (bs, 1 H, 2-H); 3.47 (bs, 1 H, 1-
H); 3.83 (s, 3 H, 8-H or 8’-H); 3.84 (s, 3 H, 8-H or 8’-H); 4.18
(m, 1 H, 4-H); 4.65 (dt, J4–5 = J3eq-5 = 11.2 Hz, J3ax-5 = 4.3 Hz,
1 H, 5-H); 7.01–7.12 (m, 3 H, 10-H + 11-H + 13-H); 7.23 (d,
J = 7.4 Hz, 1 H, 10-H). 9.10 (bs, 1 H, 15-H). 13C-NMR (Hetcor,
CDCl3, 400 MHz): 26.8 (6-C); 32.4 (3-C); 40.7 (2-C); 41.1
(1-C); 52.4(8-C and 8’-C); 56.9 (5-C); 65.9 (4-C); 108.9 (15-
C); 109.5 (13-C); 121.5 (12-C). MS (ESI+): 719.8 [2M + Na+].
5.19. (ꢃ)-(1S,2R,3S,4R)-4-(tert-butyldimethylsilyloxy)-2-
(phenylamino)cyclopentane-1,3-diol 7a and (1S,2R,3R,4R)-4-
(tert-butyldimethylsilyloxy)-3-(phenylamino)cyclopentane-
1,2-diol 8a
Starting from 500 mg (2.17 mmol) of epoxide 4, we
obtained a crude reaction product which was purified by
Biotage SP1TM (n-hexane/EtOAc from 90/10 to 0/100; SNAP
100 g column) to give 7a (377 mg, 54%) and 8a (155 mg,
22%) as brown oils.
5.19.1. 7a (Fig. 2. – S18)
[a
]D = + 21.0 [c = 1.5, CHCl3]. HRMS: C17H20N2O6Na: calcd.
371.12136; found 371.12189.
Rf = 0.5 (Hexane/EtOAc 5/5). 1H-NMR (400 MHz, CDCl3):
0.14 (s, 3 H, 3 ꢁ 6-H); 0.15 (s, 3 H, 3 ꢁ 6-H); 0.94 (s, 9 H,
9 ꢁ 8-H); 1.87 (ddt, Jgem = 14.3 Hz, J = 4.3 Hz, J = 1.1 Hz, 1 H,

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W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
5a-H); 2.26 (ddd, Jgem = 14.3 Hz, J = 6.5 Hz, J = 5.7 Hz, 1 H,
5b-H); 2.74–2.75 (2 ꢁ bs, 2 H, 2-OH + 4-OH); 3.61 (t,
9 ꢁ 8-H); 1.90 (ddd, Jgem = 14.3 Hz, J = 4.2 Hz, J = 1,3 Hz, 1 H,
5a-H); 2.28 (ddd, Jgem = 14.3 Hz, 1–5b = 6.5 Hz, J4–
J
J = 3.5 Hz,
1
H, 3-H); 3.71–3.80 (dd + bs, J = 10.3 Hz,
5b = 5.5 Hz, 1 H, 5b-H); 2.66 (d, J = 9.2 Hz, 1 H, 4-OH);
2.74 (d, J = 6.8 Hz, 1 H, 2-OH); 3.59–3.68 (m, 1 H, 3-H); 3.83
(dt, 1 H, 2-H, J1–2 = J2–3 = 4.7 Hz, J2-OH = 6.8 Hz); 3.95 (ddd,
J = 9.8 Hz, J = 7.1 Hz, J = 3.7 Hz, 1 H, 4-H); 4.27 (dd, J = 9.6 Hz,
J = 4.7 Hz, 1 H, 1-H); 4.32 (d, J = 4.3 Hz, 1 H, 9-NH); 6.68
(ddd, J = 7.8 Hz, J = 7.4 Hz, J = 1.5 Hz, 1 H, 13-H); 7.01 (dd,
J = 8.2 Hz, J = 1.4 Hz, 1 H, 15-H); 7.15–7.21 (m, 1 H, 14-H);
J = 4.8 Hz, 2 H, 9-NH + 2-H); 3.90 (bs, 1 H, 4-H); 4.24 (dd,
J = 9.8 Hz, J = 4.8 Hz, 1 H, 1-H); 6.75 (d, J12–13 = 7.3 Hz, 2 H,
13-H); 6.79 (d, J11–12 = 8.7 Hz, 2 H, 11-H); 7.20 (dd, J11–
12 = 8.7 Hz, J12–13 = 7.3 Hz,
1
H, 12-H). 13C-NMR
(100.61 MHz, CDCl3): ꢂ4.6 (6-C); ꢂ4.3 (6-C); 18.4 (7-C);
26.1 (8-C); 40.2 (5-C); 69.2 (3-C); 73.5 (1-C); 76.8 (4-C);
79.1 (2-C); 114.1 (11-C); 118.5 (13-C); 129.6 (12-C); 147.6
(10-C). MS (ESI+): 324 [M + H]+; 346 [M + Na]+.
7.26 (dd, J = 7.8 Hz, J = 1.4 Hz,
1
H, 12-H). 13C-NMR
(100.61 MHz, CDCl3): ꢂ4.6 (6-C); ꢂ4.3 (6-C); 18.4 (7-C);
26.1 (8-C); 40.1 (5-C); 69.4 (3-C); 73.5 (1-C); 76.6 (4-C);
79.1 (2-C); 113.5 (15-C); 118.7 (13-C); 120.0 (11-C); 128.4
(14-C); 129.5 (12-C); 147.0 (10-C). MS (ESI+): 358 [M + H]+.
5.19.2. 8a (Fig. 2. – S19)
5.20.2. 8b (Fig. 2. – S21)
Rf = 0.2 (Hexane/EtOAc 5/5). 1H-NMR (400 MHz, CDCl3):
0.08 (s, 3 H, 3 ꢁ 6-H); 0.09 (s, 3 H, 3 ꢁ 6-H); 0.91 (s, 9 H,
9 ꢁ 8-H); 1.91 (ddd, Jgem = 14.6 Hz, J4–5a = 4.3 Hz, J1–
5a = 2.8 Hz, 1 H, 5a-H); 2.17 (ddd, Jgem = 14.3 Hz, J1–5b = J4–
5b = 5.6 Hz, 1 H, 5b-H); 3.10 (bs, 1 H, OH); 3.20 (bs, 1 H, OH);
3.65–3.70 (m, 1 H, 2-H); 3.77 (t, J2–3 = J3–4 = 4.9 Hz, 1 H, 3-
H); 4.00 (ddd, J1–5b = 4.6 Hz, J1–5a = J1–2 = 2.8 Hz, 1 H, 1-H);
4.13–4.20 (m, 1 H, 4-H); 6.72 (d, J11–12 = 8.6 Hz, 1 H, 11-H);
6.76 (d, J12–13 = 7.3 Hz, 1 H, 13-H); 7.18 (dd, J11–12 = 8.6 Hz,
J12–13 = 7.3 Hz, 1 H, 12-H). 13C-NMR (100.61 MHz, CDCl3):
ꢂ4.6 (6-C); ꢂ4.3 (6-C); 18.2 (7-C); 26.1 (8-C); 39.8 (5-C);
68.7 (2-C); 72.8 (4-C); 78.0 (1-C); 79.6 (3-C); 114.1 (11-C);
118.5 (13-C); 129.6 (12-C); 148.0 (10-C). MS (ESI+): 324
[M + H]+; 346 [M + Na]+.
Rf = 0.5 (DCM/MeOH 9/1). 1H-NMR (400 MHz, CDCl3):
0.14(s, 3H,3 ꢁ 6-H);0.15(s, 3H,3 ꢁ 6-H);0.90(s, 9H,9 ꢁ 8-
H); 1.90–1.98 (m, 1 H, 5a-H); 2.22 (dt, Jgem = 14.6 Hz,
J = 5.7 Hz, 1 H, 5b-H); 2.74 (d, J = 6.8 Hz, 1 H, 2-OH); 3.06 (d,
J = 8.0 Hz, 1 H, 4-OH); 3.68–3.76 (m, 1 H, 3-H); 3.79–3.88 (m,
1 H, 2-H); 4.00–4.05 (m, 1 H, 4-H); 4.11–4.34 (m, 1 H, 1-H);
6.62–6.72 (m, 1 H, Ar-H); 6.91–6.95 (m, 1 H, Ar-H); 7.09–
7.17 (m, 1 H); 7.24 (dd, J = 7.9 Hz, J = 1.5 Hz, 1 H, Ar-H). 13C-
NMR (100.61 MHz, CDCl3): ꢂ4.8 (6-C); ꢂ4.5 (6-C); 18.1 (7-
C); 25.9 (8-C); 39.7 (5-C); 68.3 (3-C); 72.4 (1-C); 77.8 (4-C);
79.2 (2-C); 113.1 (15-C); 118.2 (13-C); 119.6 (11-C); 128.0
(14-C); 129.3 (12-C); 143.5 (10-C). MS (ESI+): 358 [M + H]+.
5.20. (ꢃ)-(1S,2S,4R,5S)-4-(tert-butyldimethylsilyloxy)-2-(2-
chlorophenyamino)cyclopentane-1,3-diol 7b and (ꢃ)-
(1S,2R,3R,4R)-4-(tert-butyldimethylsilyloxy)-3-(2-
chlorophenylamino)cyclopentane-1,2-diol 8b
5.21. (ꢃ)-(1S,2R,4S,5R)-2-(4-Bromophenylamino)-4-(tert-
butyldimethylsilyloxy)cyclopentane-1,3-diol 7c and (ꢃ)-
(1S,2R,4S,5R)-3-(4-bromophenylamino)-4-(tert-
Butyldimethylsilyloxy) cyclopentane-1,2-diol 8c
Starting from 500 mg (2.17 mmol) of epoxide 4, we
obtained a crude reaction product which was purified by
Biotage SP1TM (CH2Cl2/MeOH from 98/2 to 80/20; SNAP
50 g column) to give 7b (388 mg, 50%) and 8b (195 mg,
25%) as colorless oils.
Starting from 70 mg (0.304 mmol) of epoxide 4, we
obtained a crude reaction product which was purified by
Biotage SP1TM (CH2Cl2/EtOAc from 100/0 to 20/80; SNAP
50 g column) to give a mixture of 7c (49 mg, 40%) and 8c
(36 mg, 30%) as brown oils.
5.20.1. 7b (Fig. 2. – S20)
5.21.1. 7c (Fig. 2. – S22)
Rf = 0.9 (DCM/MeOH 9/1). 1H-NMR (400 MHz, CDCl3):
0.15 (s, 3 H, 3 ꢁ 6-H); 0.16 (s, 3 H, 3 ꢁ 6-H); 0.94 (s, 9 H,

W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
1295
Rf = 0.9 (DCM/MeOH 9/1). 1H-NMR (400 MHz, CDCl3):
0.14 (s, 3 H, 3 ꢁ 6-H); 0.15 (s, 3 H, 3 ꢁ 6-H); 0.93 (s, 9 H,
9 ꢁ 8-H); 1.86 (ddd, Jgem = 14.3 Hz, J = 4.3 Hz, J = 1,3 Hz, 1 H,
5a-H,); 2.23 (ddd, Jgem = 14.3 Hz, J = 6.6 Hz, J4–5b = 5.5 Hz, 1
H, 5b-H); 3.53 (dd, J2–3 = J3–4 = 3,7 Hz, 1 H, 3-H); 3.73 (t, J1–
2 = J2–3 = 4.8 Hz, 1 H, 2-H); 3.82–3.90 (m, 1 H, 4-H); 4.21
(dd, J = 4.8 Hz, J = 9.5 Hz, 1 H, 1-H); 6.67 (d, J11–12 = 8.9 Hz, 2
H, 11-H); 7.26 (d, J11–12 = 8.9 Hz, 2 H, 12-H). 13C-NMR
(100.61 MHz, CDCl3): ꢂ4.6 (6-C); ꢂ4.3 (6-C); 18.4 (7-C);
26.1 (8-C); 40.1 (5-C); 69.4 (3-C); 73.4 (1-C); 76.5 (4-C);
79.1 (2-C); 110.2 (13-C); 115.7 (11-C); 132.3 (12-C); 147.0
(10-C). MS (ESI+): 402 [M + H]+; 424 [M + Na]+.
3-H); 3.79–3.86 (m, 1 H, 2-H); 3.93–4.02 (m, 1 H, 4-H); 4.23
(dd, J = 4.8 Hz, J = 9.5 Hz, 1 H, 1-H); 6.54 (dt, J = 1.5 Hz,
J = 8.3 Hz, 1 H, Ar-H); 6.61–6.70 (m, 2 H, Ar-H + 11-H); 7.11–
7.22 (m, 1 H, Ar-H). 13C-NMR (100.61 MHz, CDCl3): ꢂ4.6 (6-
C); ꢂ4.3 (6-C); 18.4 (7-C); 26.1 (8-C); 40.1 (5-C); 69.3 (3-C);
73.2 (1-C); 76.4 (4-C); 78.8 (2-C); 101.0 (d, J = 25.8 Hz, Ar-C);
104.8 (d, J = 21.8 Hz, Ar-C); 109.9 (d, J = 2.4 Hz, Ar-C); 130.7
(d, J = 0.1 Hz, 15-C); 149.8 (d, J = 10.9 Hz, 10-C); 164.3 (d,
J = 245.4 Hz, 12-C). MS (ESI+): 342 [M + H]+; 364 [M + Na]+.
5.22.2. 8d (Fig. 2. – S25)
5.21.2. 8c (Fig. 2. – S23)
Rf = 0.2 (DCM/Hex 5/5). 1H-NMR (400 MHz, CDCl3): 0.07
(s, 3 H, 3 ꢁ 6-H); 0.08 (s, 3 H, 3 ꢁ 6-H); 0.90 (s, 9 H, 9 ꢁ 8-
H); 1.92 (ddd, Jgem = 14.7 Hz, J = 4.34 Hz, J = 2.81 Hz, 1 H, 5a-
H); 2.17 (dt, Jgem = 14.7 Hz, J1–5b = J4–5b = 5.6 Hz, 1 H, 5b-H);
2.58–3.49 (bs, 2 H, 4-OH + 3-OH); 3.61–3.67 (m, 1 H, 2-H);
3.78 (t, J1–2 = J2–3 = 5.11 Hz, 1 H, 3-H); 3.88–3.95 (m, 1 H, 1-
H); 4.11–4.19 (m, 1 H, 4-H); 6.37–6.52 (m, 3 H, Ar-H); 7.10
(dt, J = 8.2 Hz, J = 6.7 Hz, 1 H, 14-H). 13C-NMR (100.61 MHz,
CDCl3): ꢂ4.7 (6-C); ꢂ4.3 (6-C); 18.2 (7-C); 26.1 (8-C); 39.8
(5-C); 68.9 (2-C); 72.7 (4-C); 77.6 (1-C); 79.3 (3-C); 101.1
(d, J = 25.5 Hz, Ar-C); 105.1 (d, J = 21.5 Hz, Ar-C); 110,1 (d,
J = 2.3 Hz, Ar-C); 130.6 (d, J = 0.1 Hz, 15-C); 149.1 (d,
J = 10.4 Hz, 10-C); 164.3 (d, J = 243.3 Hz, 12-C). MS (ESI+):
342 [M + H]+; 364 [M + Na]+.
Rf = 0.5 (DCM/MeOH 9/1). 1H-NMR (400 MHz, CDCl3):
0.06 (s, 3 H, 3 ꢁ 6-H); 0.08 (s, 3 H, 3 ꢁ 6-H); 0.90 (s, 9 H,
9 ꢁ 8-H); 1.87–1.96 (m, 1 H, 5a-H); 2.17 (dt, Jgem = 14.6 Hz,
J1–5b = J4–5b = 5.5 Hz, 1 H, 5b-H); 3.58–3.64 (m, 1 H, 2-H);
3.75 (t, J1–2 = J2–3 = 5.03 Hz, 1 H, 3-H); 3.94–3.99 (m, 1 H, 1-
H); 4.13–4.19 (m, 1 H, 4-H); 6.61 (d, J11–12 = 8.8 Hz, 2 H, 11-
H); 7.25 (d, J11–12 = 8.8 Hz,
2
H, 12-H). 13C-NMR
(100.61 MHz, CDCl3): ꢂ4.6 (6-C); ꢂ4.3 (6-C); 18.2 (7-C);
26.1 (8-C); 39.8 (5-C); 68.9 (2-C); 72.7 (1-C); 77.9 (4-C);
80.0 (3-C); 110.1 (13-C); 115.7 (11-C); 132.2 (12-C);
146.0 (10-C). MS (ESI+): 402 [M + H]+; 424 [M + Na]+.
5.23. (ꢃ)-(1S,2R,3S,4R)-4-(tert-butyldimethylsilyloxy)-2-(2,3-
dimethylphenylamino)cyclopentane-1,3-diol 7e and (ꢃ)-
(1S,2R,3R,4R)-4-(tert-butyldimethylsilyloxy)-3-(2,3-
dimethylphenylamino)cyclopentane-1,2-diol 8e
5.22. (ꢃ)-(1S,2R,3S,4R)-4-(tert-butyldimethylsilyloxy)-2-(3-
fluorophenylamino)cyclopentane-1,3-diol 7d and (ꢃ)-
(1S,2R,3R,4R)-4-(tert-butyldimethylsilyloxy)-3-(3-
fluorophenylamino)cyclopentane-1,2-diol 8d
Starting from 50 mg (0.217 mmol) of epoxide 4, we
obtained a crude reaction product, which was purified with
Biotage SP1TM (n-hexane/AcOEt from 90/10 to 0/100; SNAP
10 g column) to give 7e (40 mg, 52%) and 8e (11 mg, 14%) as
a brown oils.
Starting from 70 mg (0.304 mmol) of epoxide 4, we
obtained a crude reaction product which was purified by
flash chromatography (first CH2Cl2/n-hexane 1/1, then
CH2Cl2/AcOEt from 95/5 to 70/30) to give 7d (66 mg, 64%)
and 8d (22 mg, 21%) as a brown oil.
5.23.1. 7e (Fig. 2. – S26)
5.22.1. 7d (Fig. 2. – S24)
Rf = 0.6 (DCM/Hex 5/5). 1H-NMR (400 MHz, CDCl3): 0.14
(s, 3 H, 3 ꢁ 6-H); 0.15 (s, 3 H, 3 ꢁ 6-H); 0.94 (s, 9 H, 9 ꢁ 8-
H); 1.89 (dt, Jgem = 14.3 Hz, J = 3.96 Hz, 1 H, 5a-H); 2.05 (s, 3
H, 3 ꢁ 16-H); 2.28 (s + m, 4H, 5b-H + 3 ꢁ 17-H); 2.66 (d,
J = 9.4 Hz, 1 H, 4-OH); 2.71 (d, J = 6.7 Hz, 1 H, 2-OH); 3.42–
3.59 (m, 1 H, 3-H); 3.59–3.67 (m, 1 H, 2-H); 3.83 (dt,
Rf = 0.5 (DCM/Hex 5/5). 1H-NMR (400 MHz, CDCl3): 0.14
(s, 3 H, 3 ꢁ 6-H); 0.15 (s, 3 H, 3 ꢁ 6-H); 0.93 (s, 9 H, 9 ꢁ 8-H);
1.87 (ddd, Jgem = 14.3 Hz, J = 4.3 Hz, J = 1,2 Hz, 1 H, 5a-H);
2.27 (ddd, Jgem = 14.3 Hz, J = 6.9 Hz, J = 5.5 Hz, 1 H, 5b-H);
2.74 (d, J = 7.1 Hz, 1 H, 2-OH); 3.58 (t, J2–3 = J3–4 = 4.2 Hz, 1 H,

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W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
J = 4.5 Hz, J = 6.6 Hz, 1 H, 4-H); 3.88–3.98 (m, 1 H, 1-H); 6.65
(d, J11–12 = 7.5 Hz, 1 H, 11-H); 6.84 (d, J12–13 = 8.1 Hz, 1 H,
13-H); 7.07 (dd, J11–12 = 7.5 Hz, J12–13 = 8.1 Hz, 1 H, 12-H).
13C-NMR (100.61 MHz, CDCl3): ꢂ4.6 (6-C); ꢂ4.3 (6-C); 12.9
(16-C); 18.4 (7-C); 21.0 (17-C); 26.1 (8-C); 40.1 (5-C); 69.4
(3-C); 73.6 (1-C); 77.0 (4-C); 79.3 (2-C); 110.1 (13-C);
120.5 (11-C); 121.1 (14-C); 126.7 (12-C); 136.8 (15-C);
145.9 (10-C). MS (ESI+): 352 [M + H]+; 374 [M + Na]+.
4-H); 4.21 (dd, J = 9.8 Hz, J = 4.8 Hz, 1 H, 1-H); 5.91–5.95 (t,
J11–13 = 2.1 Hz, 1 H, 13-H); 6.03 (d, J11–13 = 2.1 Hz, 2 H, 11-
H). 13C-NMR (100.61 MHz, CDCl3): ꢂ4.6 (6-C); ꢂ4.3 (6-C);
18.4 (7-C); 26.1 (8-C); 40.1 (5-C); 55.5 (14-C); 69.6 (3-C);
73.3 (1-C); 76.5 (4-C); 78.9 (2-C); 91.4 (13-C); 94.2 (11-C);
148.5 (10-C); 162.1 (12-C). MS (ESI+): 384 [M + H]+.
5.24.2. 8f (Fig. 2. – S29)
5.23.2. 8e (Fig. 2. – S27)
f = 0.3 (Hexane/EtOAc 5/5). 1H-NMR (400 MHz, CDCl3):
0.06(s, 3H,3 ꢁ 6-H);0.07(s, 3H,3 ꢁ 6-H);0.88(s, 9H,9 ꢁ 8-
H); 1.90 (ddd, Jgem = 14.6 Hz, J4–5a = 4.3 Hz, J1–5a = 2.9 Hz, 1 H,
5a-H); 2.17 (dt, Jgem = 14.7 Hz, J1–5b = J4–5b = 5.6 Hz, 1 H, 5b-
H); 3.63–3.68 (m, 1 H, 2-H); 3.75 (s, 3 H, 14-H); 3.83 (t, J2–
3 = J3–4 = 4.9 Hz, 1 H, 3-H); 4.04 (dt, J1–5b = 5.6 Hz, J1–5a = J1–
2 = 2.9 Hz, 1 H, 1-H); 4.13–4.18 (m, 1 H, 4-H); 5.96 (t, J11–
13 = 2.1 Hz, 1 H, 13-H); 5.99 (d, J11–13 = 2.1 Hz, 2 H, 11-H).
13C-NMR (100.61 MHz, CDCl3): ꢂ5.0 (6-C); ꢂ4.7 (6-C); 17.8
(7-C); 25.7 (8-C); 39.5 (5-C); 55.2 (14-C); 69.0 (2-C); 72.4 (4-
C); 77.2 (1-C); 78.8 (3-C); 91.2 (13-C); 93.4 (11-C); 148.1
(10-C); 161.8 (12-C). MS (ESI+): 384 [M + H]+.
Rf = 0.3 (DCM/Hex 5/5). 1H-NMR (400 MHz, CDCl3): 0.10
(s, 3 H, 3 ꢁ 6-H); 0.11 (s, 3 H, 3 ꢁ 6-H); 0.92 (s, 9 H, 9 ꢁ 8-
H); 1.95 (m, 1 H, 5a-H); 2.03 (s, 3 H, 3 ꢁ 16-H); 2.17 (dt,
Jgem = 14,5 Hz, J1–5b = J4–5b = 5.3 Hz, 1 H, 5b-H); 2.28 (s, 3 H,
3 ꢁ 17-H); 3.14 (bs, 3 H, 2-OH + 4-OH + 9-NH); 3.65–3.71
(m, 1 H, 2-H); 3.84 (t, 1 H, 3-H, J2–3 = J3–4 = 4.5 Hz); 4.02–
4.08 (m, 1 H, 1-H); 4.17–4.24 (m, 1 H, 4-H); 6.64 (d, J11–
12 = 7.5 Hz, 1 H, 11-H); 6.70 (d, J12–13 = 8.0 Hz, 1 H, 13-H);
7.02 (dd, J11–12 = 7.5 Hz, J12–13 = 8.0 Hz, 1 H, 12-H). 13C-
NMR (100.61 MHz, CDCl3): ꢂ4.6 (6-C); ꢂ4.3 (6-C); 12.9
(16-C); 18.2 (7-C); 21.0 (17-C); 26.1 (8-C); 39.7 (5-C); 69.3
(2-C); 73.4 (4-C); 78.3 (1-C); 80.3 (3-C); 110.1 (13-C);
120.5 (11-C); 121.1 (14-C); 126.5 (12-C); 137.0 (15-C);
145.4 (10-C). MS (ESI+): 352 [M + H]+; 374 [M + Na]+.
5.25. (ꢃ)-2-chloro-N-phenyl-N-((1R,2S,3R,5S)-2,3,5-tris(tert-
butyldimethylsilyloxy)cyclopentyl) acetamide 10
2,6-Lutidine (0.224 mL, 1.920 mmol) and TBDMSOTf
(372 mg, 1.408 mmol) were added at 0 8C to a stirred
solution of 7a (207 mg, 0.640 mmol) and 8a (207 mg,
0.640 mmol) in CH2Cl2 (4 mL). The mixture was stirred for
1 h at room temperature, and then the reaction was
quenched with a saturated NH4Cl solution. The organic
layer was washed once with a saturated NH4Cl solution
and twice with brine, dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude product
was purified by flash chromatography (n-hexane/ CH2Cl2
from 100/0 to 88/12) to give pure silylether intermediate
(577 mg, 82%) as a colorless oil.
5.24. (ꢃ)-(1S,2R,3S,4R)-4-(tert-butyldimethylsilyloxy)-2-(3,5-
dimethoxyphenylamino)cyclopentane-1,3-diol 7f and (ꢃ)-
(1S,2R,3R,4R)-4-(tert-butyldimethylsilyloxy)-3-(3,5-
dimethoxyphenylamino)cyclopentane-1,2-diol 8f
Starting from 100 mg (0.434 mmol) of epoxide 2, we
obtained a crude reaction product which was purified with
Biotage SP1TM (n-hexane/AcOEt from 90/10 to 0/100; SNAP
50 g column) to give a mixture of 7f (96 mg, 58%) and 8f
(36 mg, 22%) as brown oils.
5.24.1. 7f (Fig. 2. – S28)
5.26. Silylether intermediate (Fig. 2. – S30)
Rf = 0.6 (Hexane/EtOAc 5/5). 1H-NMR (400 MHz, CDCl3):
0.13 (s, 3 H, 3 ꢁ 6-H); 0.14 (s, 3 H, 3 ꢁ 6-H); 0.93 (s, 9 H,
9 ꢁ 8-H); 1.86 (ddt, Jgem = 14.2 Hz, J = 4.4 Hz, J = 1.1 Hz, 1 H,
5a-H); 2.26 (ddd, Jgem = 14.2 Hz, J = 6.6 Hz, J = 5.5 Hz, 1 H,
5b-H); 3.55 (t, J = 3.8 Hz, 1 H, 3-H); 3.74 (s, 3 H, 14-H); 3.75
(s, 3 H, 14-H); 3.76–3.80 (m, 1 H, 2-H); 3.88–3.93 (m, 1 H,
Rf = 0.9 (Hexane/EtOAc 9/1). 1H-NMR (400 MHz, CDCl3):
ꢂ0.05 + 0.00 + 0.04 + 0.06 + 0.07 + 0.08 (6 s, 6 ꢁ 3 H, 6 ꢁ 6-
H + 6 ꢁ 6’-H + 6 ꢁ 6’’-H); 0.87 + 0.88 + 0.92 (3 s, 3 ꢁ 9 H,
9 ꢁ 8-H + 9 ꢁ 8’-H + 9 ꢁ 8’’-H); 1.81 (ddd, Jgem = 13.4 Hz, J1-

W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
1297
5a = J4–5a = 5.7 Hz, 1 H, 5a-H); 2.20 (ddd, Jgem = 13.4 Hz,
0.420 mmol),
di-tert-butyl(naphthalen-1-yl)phosphine
J = 8.2 Hz, J = 5.6 Hz, 1 H, 5b-H); 3.64–3.70 (m, 1 H, 2-H);
3.73 (dd, J2–3 = J3–4 = 5.0 Hz, 1 H, 3-H); 3.81–3.89 (m, 1 H, 4-
H); 3.93–4.02 (m, 1 H, 1-H); 6.66–6.82 (m, 3 H, 2 ꢁ 11-
H + 13-H);7.15(dd, J = 8.7Hz, J = 7.3 Hz,2H, 12-H). 13C-NMR
(100.61 MHz, CDCl3): ꢂ4.6 + ꢂ4.4 + ꢂ4.2 + ꢂ4.1 + ꢂ3.9
(2 ꢁ 6-C + 2 ꢁ 6’-C + 2 ꢁ 6’’-C); 18.2 + 18.48 + 18.49 (7-
C + 7’-C + 7’’-C); 26.1 + 26.2 + 26.3 (8-C + 8’-C + 8’’-C); 40.8
(5-C);67.6(3-C, onlyonHSQC);73.0(1-C);76.6(4-C, onlyon
HSQC); 78.5 (2-C, only on HSQC); 114.4 (11-C, only on
HSQC); 117.9 (13-C, only on HSQC); 129.5 (12-C, only on
HSQC); (10-C, not visible on HSQC). MS (ESI+): 552 [M + H]+.
(252 mg, 0.924 mmol) in toluene (1 mL). The mixture was
stirredfor6 hat100 8C, thenfilteredthroughacelitepadand
evaporated under reduced pressure. The residue was
purified by flash chromatography (n-hexane/CH2Cl2 from
95/5 to 40/60) to give 12 (174 mg, 70%) as a white solid.
Rf = 0.3 (Hexane/EtOAc 93/7). 1H-NMR (400 MHz, CDCl3):
ꢂ0.27 + ꢂ0.25 + ꢂ0.12 + ꢂ0.07 + 0.09 + 0.10 (6 s, 6 ꢁ 3 H,
6 ꢁ 6-H + 6 ꢁ 6’-H + 6 ꢁ 6’’-H); 0.69 + 0.74 + 0.97 (3 s, 3 ꢁ 9
H, 9 ꢁ 8-H + 9 ꢁ 8’-H + 9 ꢁ 8’’-H); 1.66–1.75 (m, 1 H, 5a-H);
2.29 (ddd, 1 H, 5b-H, Jgem = 14.3 Hz, J = 8.6 Hz, J = 4.4 Hz);
3.42 (d, 1 H, 17a-H, Jgem = 22.4 Hz); 3.48 (d, 1 H, 17b-H,
Jgem = 22.4 Hz); 4.01–4.08 (m, 1 H, 1-H); 4.39 (dd, 1 H, 3-H,
J2–3 = 9.3 Hz, J3–4 = 6.3 Hz); 4.57 (dd, 1 H, 2-H, J2–3 = 9.3 Hz,
J1–2 = 4.1 Hz); 4.79–4.86 (m, 1 H, 4-H); 6.89 (d, 1 H, 13-H,
J = 8.0 Hz); 6.96 (t, 1 H, 12-H, J = 7.5 Hz); 7.18 (d, 1 H, 10-H,
J = 7.3 Hz); 7.20–7.26 (m, 1 H, 11-H). 13C-NMR (100.61 MHz,
CDCl3): ꢂ5.0 + ꢂ4.9 + ꢂ4.7 + ꢂ4.2 + ꢂ4.3 + ꢂ4.0 (2 ꢁ 6-
C + 2 ꢁ 6’-C + 2 ꢁ 6’’-C); 18.1 + 18.5 (7-C + 7’-C + 7’’-C);
25.9 + 26.0 + 26.3 (8-C + 8’-C + 8’’-C); 36.7 (15-C); 40.9 (5-
C); 67.7 (3-C); 69.1 (4-C); 72.6 (1-C); 73.5 (2-C); 109.3 (13-
C); 122.1 (12-C); 124.3 (14-C); 124.4 (10-C); 128.1 (11-C);
146.5 (9-C); 176.1 (16-C). MS (ESI+): 614 [M + Na]+. HRMS:
Chloroacetyl chloride (145
mL, 1.812 mmol) and 2,6-
lutidine (264 L, 2.264 mmol) were added to a stirred
m
solution of silylether intermediate (500 mg, 0.906 mmol)
in dry toluene (2 mL) under N2 atmosphere. The reaction
was stirred for 45 min at room temperature, then was
diluted with CH2Cl2 and washed three times with water.
The organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude residue
was purified with Biotage SP1TM (n-hexane/EtOAc from 98/
2 to 80/20; SNAP 50 g column) to give pure 10 (545 mg,
96%) as a white solid.
C31H57NO4Si3Na: calcd. 614.34876; found 614.34797.
5.28. (ꢃ)-(Z)-3-(4-isopropylbenzylidene)-1-((1R,2S,3R,5S)-
2,3,5-tris(tert-butyldimethylsilyloxy)cyclopentyl)indolin-2-one
15Z and (ꢃ)-(E)-3-(4-isopropylbenzylidene)-1-((1R,2S,3R,5S)-
2,3,5-tris(tert-butyldimethylsilyloxy)cyclopentyl)indolin-2-one
15E
4-Isopropylbenzaldehyde (14
mL, 0.093 mmol) and
Rf = 0.64(Hexane/EtOAc9/1).1H-NMR(400 MHz,CDCl3):
piperidine (0.8 L, 8.45 mol) were added to a stirred
m
m
0.03 + 0.04 + 0.05 + 0.07 (6 s,
6
3
H, 6 ꢁ 6-H + 6 ꢁ 6’-
solution of 12 (50 mg, 0.084 mmol) in MeOH (5 mL). The
reaction was stirred at room temperature for 2 h to give a
yellow solution. After reaction completion, the solvent was
evaporated under reduced pressure and the residue was
purified with Biotage SP1TM (n-hexane/CH2Cl2 from 90/10
to 0/100; SNAP 10 g column) to give 15Z (10 mg, 16%) and
15E (39 mg, 64%), as yellow solids.
H + 6 ꢁ 6’’-H); 0.84 + 0.90 (3 s, 3 ꢁ 9 H, 9 ꢁ 8-H + 9 ꢁ 8’-
H + 9 ꢁ 8’’-H); 1.52–1.67 (m, 1 H, 5a-H); 2.24 (ddd, 1 H,
5b-H,Jgem = 13.5 Hz,J = 8.4 Hz,J = 4.7 Hz);3.81(d, 1 H, 17a-H,
Jgem = 13.2 Hz); 3.88 (d, 1 H, 17b-H, Jgem = 13.2 Hz); 3.93 (dd,
1 H, 3-H, J2-3 = 6.7 Hz, J3–4 = 8.9 Hz); 4.03 (dd, 1 H, 1-H,
J = 7.3 Hz, J3–4 = 4.3 Hz); 4.73 (dd, 1 H, 2-H, J = 8.9 Hz, J3–
4 = 4.1 Hz); 4.81–4.89 (m, 1 H, 4-H);7.28–7.43 (m, 5H, Ar-H).
13C-NMR (100.61 MHz, CDCl3): ꢂ4.5 + ꢂ4.3 + ꢂ4.2 +
ꢂ4.0 + ꢂ3.9 + ꢂ3.8 (2 ꢁ 6-C + 2 ꢁ 6’-C + 2 ꢁ 6’’-C); 18.1 +
18.3 + 18.4 (7-C + 7’-C + 7’’-C); 26.1 + 26.3 + 26.4 (8-C + 8’-
C + 8’’-C); 40.9 (5-C); 43.3 (14-C);69.2 (4-C); 73.0 (1-C); 76.6
(2-C); 78.5 (3-C); 127.9 (Ar-C); 128.2 (Ar-C); 129.7 (Ar-C);
144.6 (10-C); 166.5 (13-C). MS (ESI+): 650 [M + Na]+.
5.28.1. 15Z (Fig. 2. – S33)
Rf = 0.7 (Hexane/DCM 6/4). 1H-NMR (400 MHz, CDCl3):
ꢂ0.28 + ꢂ0.26 + ꢂ0.13 + ꢂ0.07 + 0.10 + 0.11 (6 s, 6 ꢁ 3 H,
6 ꢁ 6-H + 6 ꢁ 6’-H + 6 ꢁ 6’’-H); 0.68 + 0.74 + 0.98 (3 s, 3 ꢁ 9
H, 9 ꢁ 8-H + 9 ꢁ 8’-H + 9 ꢁ 8’’-H); 1.28 (d,
6
H, 23-H,
H, 5a-H, Jgem = 14.3 Hz, J4–
5a = 2.6 Hz, J1–5a = 2.0 Hz); 2.33 (ddd, H, 5b-H,
5.27. (ꢃ)-1-((1R,2S,3R,5S)-2,3,5-tris(tert-
butyldimethylsilyloxy)cyclopentyl) indolin-2-one 12
(Fig. 2. – S32)
J = 6.9 Hz); 1.71 (ddd, 1
1
Jgem = 14.3 Hz, J4–5b = 8.5 Hz, J1–5b = 4.3 Hz); 2.96 (sp, 1 H,
22-H, J = 6.9 Hz); 4.08 (ddd, 1 H, 1-H, J1–5b = 4.1 Hz, J1–
2 = 4.0 Hz, J1–5a = 2.0 Hz); 4.38–4.52 (m, 1 H, 3-H); 4.69 (dd,
1 H, 2-H, J2–3 = 9.4 Hz, J1–2 = 4.0 Hz); 4.88 (ddd, 1 H, 4-H, J4–
Palladium(II) acetate (18.86 mg, 0.084 mmol) was added
under N2 atmosphere to a stirred solution of 10 (264 mg,

1298
W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
5b = 8.5 Hz, J3–4 = 6.3 Hz, J4–5a = 2.6 Hz); 6.88 (d, 1 H, 13-H,
J = 7.9 Hz); 6.98 (dt, 1 H, 11-H, J = 7.6 Hz, J = 0.9 Hz); 7.22
(dt, 1 H, 12-H, J = 7.8 Hz, J = 1.2 Hz); 7.32 (d, 2 H, 20-H,
J = 8.3 Hz); 7.47 (dd, 1 H, 10-H, J = 7.6 Hz, J = 0.7 Hz); 7.50 (s,
1 H, 17-H) 8.20 (d, 1 H, 19-H, J = 8.3 Hz). 13C-NMR
(100.61 MHz, CDCl3): ꢂ4.9 + ꢂ4.8 + ꢂ4.7 + ꢂ4.3 + ꢂ4.2 +
ꢂ4.0 (2 ꢁ 6-C + 2 ꢁ 6’-C + 2 ꢁ 6’’-C); 18.1 + 18.5 (7-C + 7’-
C + 7’’-C); 24.0 + 24.1 + 24.2 (8-C + 8’-C + 8’’-C); 40.9 (5-C);
67.8 (3-C); 69.3 (4-C); 72.7 (1-C); 73.4 (2-C); 109.0 (13-C);
118.9 (10-C); 121.8 (12-C); 127.0 (20-C); 129.9 (11-C);
132.1 (9-C); 132.3 (19-C); 137.0 (17-C); 152.0 (15-C);
169.4(16-C). MS (ESI+): 744 [M + Na]+.
layers were then evaporated under reduced pressure. The
residue was purified with Biotage SP1TM (n-hexane/
acetone from 88/12 to 0/100; SNAP 10 g column) to give
16 in a Z/E 40/60 mixture (11.6 mg, 74%) as a yellow solid.
Rf = 0.3 + 0.2 (Hexane/Acetone 5/5). 1H-NMR (400 MHz,
CD3OD): 1.46 (d, 6 H, 23-H Z-isomer, J = 6.9 Hz); 1.48 (d, 6
H, 23-H, Z-isomer, J = 6.9 Hz); 1.94–2.02 (m, 1 H, 5a-H);
2.69 (ddd, 1 H, 5b-H, Jgem = 14.2 Hz, J = 8.4 Hz, J = 5.6 Hz);
3.15 (sp, 1 H, 19-H, J = 6.9 Hz); 4.31–4.38 (m, 1 H, 1-H); 4.64
(dd, 1 H, 3-H, J = 15.5 Hz, J = 7.0 Hz); 4.81 (dd, 1 H, 2-H,
J = 8.8 Hz, J = 4.0 Hz); 4.85–4.93 (m, 1 H, 4-H); 7.03–7.12
(m, 1 H, 9-H Z-isomer); 7.18–7.26 (m, 2 H, 9-H Z-
isomer + 10-H E-isomer); 7.25–7.31 (d, 1 H, 10-H E-isomer,
J = 8.0 Hz); 7.40–7.51 (m, 2 H, Ar-H); 7.52–7.60 (m, 1 H, Ar-
H); 7.76–7.92 (m, 3 H, Ar-H); 8.44 (d, 1 H, 14-H Z-isomer,
J = 8.3 Hz). 13C-NMR (100.61 MHz, CD3OD): 24.1 + 24.2 (20-
C); 35.4 + 35.5 (19-C); 40.2 (5-C); 67.8 + 67.8 (3-C); 69.8 (4-
C); 71.0 + 71.1 (1-C); 73.1 (2-C); 109.9 + 110.6 (10-C);
118.9 (10-C); 129.7 (Ar-CH); 130.7 + 130.8 (Ar-CH); 133.3
(CIV); 133.5 (Ar-CH); 133.6 (CIV); 138.3 (Ar-CH); 138.5 (Ar-
5.28.2. 15E (Fig. 2. – S34)
CH);
168.3 + 170.7 (16-C). MS (ESI+): 744 [M + Na]+. HRMS:
23H25NO4Na: calcd. 402.16758; found 402.16725.
143.6 + 145.6
(CIV);
152.6 + 153.2
(12-C);
C
Rf = 0.4 (Hexane/EtOAc 6/4). 1H-NMR (400 MHz, CDCl3):
ꢂ0.26 + ꢂ0.25 + ꢂ0.11 + ꢂ0.06 + 0.10 + 0.12 (6 s, 6 ꢁ 3 H,
6 ꢁ 6-H + 6 ꢁ 6’-H + 6 ꢁ 6’’-H); 0.69 + 0.76 + 0.98 (3 s, 3 ꢁ 9
H, 9 ꢁ 8-H + 9 ꢁ 8’-H + 9 ꢁ 8’’-H); 1.30 (d,
6
H, 23-H,
H, 5a-H, Jgem = 14.1 Hz, J4–
5a = 2.9 Hz, J1–5a = 2.6 Hz); 2.32 (ddd, H, 5b-H,
J = 6.9 Hz); 1.73 (ddd,
1
1
Jgem = 14.1 Hz, J4–5b = 8.6 Hz, J1–5b = 4.4 Hz); 2.98 (sp, 1 H,
22-H, J = 6.9 Hz); 4.07–4.11 (m, 1 H, 1-H); 4.42 (dd, 1 H, 3-H,
J2–3 = 9.0 Hz, J3–4 = 6.3 Hz); 4.62 (dd, 1 H, 2-H, J2–3 = 9.0 Hz,
J1–2 = 3.9 Hz); 4.88 (ddd, 1 H, 4-H, J4–5b = 8.6 Hz, J3–4 = 6.3 Hz,
J4–5a = 2.9 Hz); 6.84 (dt, 1 H, 11-H, J = 7.6 Hz, J = 1.0 Hz); 6.91
(d, 1 H, 13-H, J = 8.1 Hz); 7.22 (dt, 1 H, 12-H, J = 7.8 Hz;
J = 1.2 Hz); 7.32 (d, 2 H, 20-H, J = 8.4 Hz); 7.63 (d, 1 H, 19-H,
J = 7.9 Hz); 7.71 (d, 1 H, 10-H, J = 6.6 Hz); 7.74 (s, 1 H, 17-H).
13C-NMR (100.61 MHz, CDCl3): ꢂ4.9 + ꢂ4.8 + ꢂ4.7 + ꢂ4.3 +
ꢂ4.2 + ꢂ4.0 (2 ꢁ 6-C + 2 ꢁ 6’-C + 2 ꢁ 6’’-C); 18.1 + 18.5 (7-
C + 7’-C + 7’’-C); 25.9 + 26.0 + 26.3 (8-C + 8’-C + 8’’-C); 41.0
(5-C); 67.9 (3-C); 69.7 (4-C); 72.6 (1-C); 73.9 (2-C); 109.4
(13-C); 121.5 (12-C); 122.9 (10-C); 127.0 (20-C); 129.9 (11-
C); 130.0 (19-C); 132.9 (9-C); 136.9 (17-C); 151.2 (15-C);
169.4(16-C). MS (ESI+): 744 [M + Na]+.
5.30. (ꢃ)-2-chloro-N-((1R,2S,3R,5S)-2,3,5-tris(tert-
butyldimethylsilyloxy)cyclopentyl)aniline 19 (Fig. 2. – S36)
TBDMSOTf (302
mL, 1.314 mmol) was added at 0 8C to a
solution of 2,6-lutidine (218
ml, 1.877 mmol), 7b (224 mg,
0.626 mmol) and 8b (224 mg, 0.626 mmol) in dry THF
(4 mL). The solution was stirred for 2 h, the solvent was
removed under reduced pressure and the residue was taken
up in Et2O (4 mL). The organic layer was washed two times
with water, dried over Na2SO4, filtered and evaporated
under reduced pressure. The residue was purified by flash
chromatography on silica gel (n-hexane/CH2Cl2 from 100/0
to 85/15) to give pure 19 (493 mg, 68%) as a white solid.
Rf = 0.5 (Hexane/DCM 9/1). 1H-NMR (400 MHz, CDCl3):
ꢂ0.09 + ꢂ0.01 + ꢂ0.01 + 0.05 + 0.08 (5 s, 6 ꢁ 3 H, 6 ꢁ 6-
H + 6 ꢁ 6’-H + 6 ꢁ 6’’-H); 0.85 + 0.86 + 0.93 (3 s, 3 ꢁ 9 H,
9 ꢁ 8-H + 9 ꢁ 8’-H + 9 ꢁ 8’’-H); 1.75 (dt, 1 H, 5a-H, Jgem
=
13.8 Hz, J = 4.4 Hz); 2.15 (ddd, 1 H, 5b-H, Jgem = 13.8 Hz,
J = 8.3 Hz, J = 5.3 Hz); 3.65 (dd, 1 H, 2-H, J = 7.2 Hz, J = 3.7 Hz);
3.84–3.95 (m, 2 H, 3-H + 4-H); 3.98 (dd, 1 H, 1-H, J = 9.0 Hz,
J = 4.1 Hz); 6.59 (ddd, 1 H, 13-H, J = 7.9 Hz, J = 7.4 Hz,
J = 1.5 Hz); 7.00 (dd, 1 H, 15-H, J = 8.3 Hz, J = 1.5 Hz); 7.05–
7.10 (m, 1 H, 14-H); 7.20 (dd, 1 H, 12-H, J = 7.9 Hz, J = 1.5 Hz).
13C-NMR (100.61 MHz, CDCl3): ꢂ4.7 + ꢂ4.5 + ꢂ4.2 + ꢂ4.1 +
ꢂ4.0 + ꢂ3.9 (2 ꢁ 6-C + 2 ꢁ 6’-C + 2 ꢁ 6’’-C); 18.2 + 18.47 +
18.52 (7-C + 7’-C + 7’’-C); 26.1 + 26.2 + 26.3 (8-C + 8’-C + 8’’-
C); 41.0 (5-C); 66.5 (3-C); 72.8 (1-C); 77.4 (4-C); 78.7 (2-C);
113.6 (11-C); 117.3 (13-C); 119.0 (15-C); 127.9 (12-C);
129.0 (14-C); 144.5 (10-C). MS (ESI+): 586 [M + H]+.
5.29. (ꢃ)-(Z and E)-3-(4-isopropylbenzylidene)-1-
((1R,2S,3R,5S)-2,3,5-trihydroxycyclopentyl)indolin-2-one 16
TBAF (0.127 mL, 0.127 mmol, 1 M solution in THF) was
added to a stirred solution of 15Z and 15E mixture (30 mg,
0.041 mmol). The solvent was evaporated under reduced
pressure and taken up with CH2Cl2. The organic layer was
washed four times with water, the combined organic

W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
1299
the crude product was taken up in CH2Cl2 and filtered on a
celite pad. The filtrate was washed twice with water, dried
over Na2SO4, filtered and concentrated under reduced
pressure. The crude was purified with Biotage SP1TM (n-
hexane/EtOAc from 90/10 to 50/50) to give pure 22
(187 mg, 69%) as a yellow oil. Rf = 0.5 (Hexane/EtOAc 8/2).
1H-NMR (400 MHz, CDCl3): ꢂ0.34 + ꢂ0.14 + ꢂ0.09 + 0.11 +
0.12 (6 s, 6 ꢁ 3 H, 6 ꢁ 6-H + 6 ꢁ 6’-H + 6 ꢁ 6’’-H); 0.65 +
0.73 + 0.98 (3 s, 3 ꢁ 9 H, 9 ꢁ 8-H + 9 ꢁ 8’-H + 9 ꢁ 8’’-H);
1.72 (ddd, Jgem = 14.2 Hz, J4–5a = 2.6 Hz, J1–5a = 2.0 Hz, 1 H,
5a-H); 2.34 (ddd, Jgem = 14.2 Hz, J4–5b = 8.6 Hz, J1–
5b = 4.4 Hz, 1 H, 5b-H); 4.08 (bs, 1 H, 1-H); 4.56 (dd, J2–
3 = 9.6 Hz, J3–4 = 6.0 Hz, 1 H, 3-H); 4.61 (dd, J2–3 = 9.6 Hz, J1–
2 = 4.1 Hz, 1 H, 2-H); 4.90 (ddd, J4–5b = 8.6 Hz, J3–4 = 6.0 Hz,
J4–5a = 2.6 Hz, 1 H, 4-H); 6.99–7.09 (m, 4H, 10-H + 11-
5.31. (ꢃ)-2-chloro-N-((1R,2S,3R,5S)-2,3,5-tris(tert-
butyldimethylsilyloxy)cyclopentyl)aniline 20
A solution of 19 (363 mg, 0.619 mmol) in THF (2 mL) was
slowly added to
a stirred solution of Chlorosulfonyl
isocyanate (0.081 mL, 0.928 mmol) in THF (1 mL) at
ꢂ10 8C. The reaction mixture was stirred 10 min at
ꢂ10 8C, then quenched with water and stirred for 30 min,
then NaOH (3 M) was added. The organic layer was diluted
with AcOEt and washed 2 times with brine, dried over
Na2SO4, filtered and concentrated under reduced pressure.
The residue was purified with Biotage SP1TM (n-hexane/
AcOEt from 100/0 to 60/40, SNAP 10 g column) to give pure
20 (362 mg, 93%) as a white solid. Rf = 0.5 (Hexane/EtOAc 7/
3). 1H-NMR (400 MHz, C6D6): 0.09 + 0.11 + 0.12 + 0.14 +
0.17 + 0.18 + 0.21 + 0.22 + 0.26 + 0.27 (10 s for 2 rotamers,
6 ꢁ 3 H, 6 ꢁ 6-H + 6 ꢁ 6’-H + 6 ꢁ 6’’-H); 0.93 + 0.95 + 0.99 +
1.02 + 1.11 (5 s for 2 rotamers, 3 ꢁ 9 H, 9 ꢁ 8-H + 9 ꢁ 8-
H’ + 9 ꢁ 8’’-H); 1.70–1.81 (m, 0.6 H for 1 rotamer, 5a-H);
2.12–2.37 (m, 1.4H, 1 ꢁ 5b-H + 0.4 ꢁ 5a-H); 3.92 (d, 0.4H, 3-
H, J = 3.9 Hz); 4.07 (bs, 2 H, NH2); 4.14 (dd, 0.6 H, 3-H,
J = 8.5 Hz, J = 5.7 Hz); 4.76–4.89 (bs, 1 H, 1-H); 4.94–5.05 (m,
1 H, 2-H); 5.12–5.24 (m, 1 H, 4-H); 6.56–6.71 (m, 1 H, Ar-H);
6.78–6.93 (m, 1 H, Ar-H); 7.05 (d, 1 H, Ar-H, J = 8.0 Hz); 7.65
(d, 0.4H, Ar-H, J = 7.8 Hz); 7.70 (d, 0.6 H, Ar-H, J = 7.8 Hz). 13C-
NMR (100.61 MHz, C6D6): ꢂ4.6 + ꢂ4.4 + ꢂ4.3 + ꢂ4.0 +
ꢂ3.9 + ꢂ3.8 + ꢂ3.3 (2 ꢁ 6-C + 2 ꢁ 6’-C + 2 ꢁ 6’’-C for the 2
rotamers); 18.1 + 18.4 + 18.5 (7-C + 7’-C + 7’’-C); 26.1 +
26.2 + 26.3 + 26.5 + 26.6 (8-C + 8’-C + 8’’-C for the 2 rota-
H + 12-H + 13-H); 8.96 (bs,
1
H, 15-H). 13C-NMR
(100.61 MHz, CDCl3): ꢂ5.5 + ꢂ5.3 + ꢂ5.1 + ꢂ4.7 + ꢂ4.6 +
ꢂ4.4 (2 ꢁ 6-C + 2 ꢁ 6’-C + 2 ꢁ 6’’-C); 17.7 + 17.8 + 18.1 (7-
C + 7’-C + 7’’-C); 25.5 + 25.6 + 25.9 (8-C + 8’-C + 8’’-C); 40.5
(5-C); 67.6 (3-C); 69.1 (4-C); 72.3 (1-C); 73.3 (2-C); 108.4
(13-C); 108.9 (12-C); 121.0 (10-C); 121.3 (11-C); 127.2
(14-C); 132.1 (9-C); 154.8 (16-C). MS (ESI+): 593 [M + H]+;
615 [M + Na]+.
5.33. (ꢃ)-1-((1R,2S,3R,5S)-2,3,5-trihydroxycyclopentyl)1H-
benzo[d]imidazol-2(3H)-one 23 (Fig. 2. – S39)
Hydrochloric acid (0.464 mmol, 23
mL, 20 M solution in
MeOH) was added to a stirred solution of 22 (83.3 mg,
0.140 mmol) in MeOH (3 mL). The reaction was stirred for
3 h at room temperature, and then the solvent was
removed under reduced pressure. The residue was taken
up with distilled water and washed three times with
CH2Cl2. The aqueous phase was evaporated under reduced
pressure and pure 23 (35 mg, quantitative yield) was
obtained as a white solid without further purification. 1H-
NMR (400 MHz, CD3OD): 1.82 (ddd, Jgem = 14.4 Hz, J4-
mers); 40.5 + 40.6 (5-C for the
2 rotamers); 71.5 +
72.0 + 72.1 + 72.6 + 73.7 + 78.3 + 78.4 + 80.9 (3-C + 4-C + 1-
C + 2-C for the 2 rotamers); 128.2 (Ar-C); 128.4 (Ar-C);
130.5 (Ar-C); 131.0 (Ar-C); 133.1 (Ar-C); 142.8 (Ar-C); 156.4
(15-C). MS (ESI+): 629 [M + H]+.
5a = 5.4 Hz, J1–5a = 3.4 Hz,
Jgem = 14.4 Hz, J1–5b = 8.5 Hz, J4–5b = 5.4 Hz, 1 H, 5b-H);
4.15–4.20 (m, H, 1-H); 4.56 (dd, J2–3 = 8.9 Hz, J3–
1
H, 5a-H); 2.55 (ddd,
1
4 = 7.7 Hz, 1 H, 3-H); 4.62 (dd, J2–3 = 8.9 Hz, J1–2 = 5.0 Hz,
1 H, 2-H); 4.67–4.77 (m, 1 H, 4-H); 6.32–6.44 (m, 3 H,
5.32. (ꢃ)-1-((1R,2S,3R,5S)-2,3,5-tris(tert-
butyldimethylsilyloxy)cyclopentyl)1H-benzo[d]imidazol-2(3H)-
one 22
3 ꢁ Ar-H); 6.98–7.06 (m,
1
H, Ar-H). 13C-NMR
(100.61 MHz, CD3OD): 40.0 (5-C); 67.7 (3-C); 69.8 (4-C);
70.8 (1-C); 73.1 (2-C); 109.8 (13-C); 110.3 (12-C); 122.3
(10-C); 122.4 (11-C); 129.6 (14-C); 132.2 (9-C); 156.8 (16-
C). MS (ESI+): 273 [M + Na]+; 523 [2M + Na]+. HRMS:
DIPEA (0.195 mL, 1.122 mmol), palladium(II) acetate
(8 mg, 0.036 mmol) and 2-dicyclohexylphosphino-2’,4’,6’-
triisopropylbiphenyl (178 mg, 0.373 mmol) were added to
a stirred solution of 20 (235 mg, 0.373 mmol) in 2-
propanol (3 mL) under N2 atmosphere at room tempera-
ture. The mixture was stirred at reflux overnight, and then
C12H14N2O4Na: calcd. 273.08458; found 273.08455.
6. Conflicts of interest
There is no conflict of interest for all the authors.

1300
W. Hatton et al. / C. R. Chimie 13 (2010) 1284–1300
[4] S. Le Corre, H.W. Klafki, N. Plesnila, G. Huebinger, A. Obermeier, H.
Acknowledgements
Sahagun, B. Monse, P. Seneci, J. Lewis, J. Eriksen, C. Zehr, M. Yue, E.
McGowan, D.W. Dickson, M. Hutton, H.M. Roder, Proc. Natl Acad. Sci. U.
S. A. 103 (2006) 9673.
This work was financially supported in part by the
[5] (a) K.M. Sakamoto, Curr. Opin. Investig. Drugs 5 (2004) 1329 ;
(b) A. Hammach, A. Barbosa, F.C. Gaenzler, T. Fadra, D. Goldberg, M.-H.
Hao, R.R. Kroe, P. Liu, K.C. Qian, M. Ralph, C. Sarko, F. Soleymanzadeh, N.
Moss, Bioorg. Med. Chem. Lett. 16 (2006) 6316.
`
Italian ‘‘Ministero dell’Universita e della Ricerca’’ (MiUR,
Grant number RBPR05NWWC_004).
[6] (a) A. Bernardi, D. Arosio, L. Manzoni, F. Micheli, A. Pasquarello, P.
Seneci, J. Org. Chem. 66 (2001) 6209 ;
Appendix A. Supplementary data
(b) J.J. Reina, S. Sattin, D. Invernizzi, S. Mari, L. Martinez-Prats, G.
Tabarani, F. Fieschi, R. Delgado, P.M. Nieto, J. Rojo, A. Bernardi, Chem.
Med. Chem. 2 (2007) 1030.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.crci.2009.11.004.
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