Amino-zinc-ene-enolate cyclization: A short access to cis-3-substituted prolino-homotryptophane derivatives

Article abstract of DOI:10.1021/jo801006a

(Chemical Equation Presented) Proline chimeras are useful tools for medicinal chemistry and/or biological applications. The asymmetric synthesis of cis-3-substituted prolines can be easily achieved via amino-zinc-ene-enolate cyclization followed by transm

Full text of DOI:10.1021/jo801006a

Amino-Zinc-Ene-Enolate Cyclization: A Short Access to
cis-3-Substituted Prolino-homotryptophane Derivatives
Ce´line Mothes,†,‡,§ Solange Lavielle,†,‡ and Philippe Karoyan*,†,‡
UPMC UniV Paris 06, UMR 7613 and FR2769, CNRS, UMR 7613 and FR2769, Synthe`se, Structure et
Fonction de Mole´cules BioactiVes, Fe´de´ration de Chimie Mole´culaire, UPMC, 4, Place Jussieu, 75252,
Paris Cedex 05, France, and Genzyme Pharmaceuticals, Eichenweg 1, CH-4410 Liestal, Switzerland
philippe.karoyan@upmc.fr
ReceiVed May 9, 2008
Proline chimeras are useful tools for medicinal chemistry and/or biological applications. The asymmetric
synthesis of cis-3-substituted prolines can be easily achieved via amino-zinc-ene-enolate cyclization
followed by transmetalation of the cyclic zinc intermediate for further functionalization. Syntheses of
prolino-homotryptophane derivatives were achieved through Negishi cross-coupling of the zinc intermediate
with indole rings. The use of Pd catalyst derived from Fu’s [(t-Bu3)PH]-BF4 was required to avoid the
undesired ꢀ-hydride elimination. Optically pure and orthogonally protected compounds were obtained
readily usable for peptide synthesis.
Introduction
ꢀ-turn,4 incorporation of cis-3-substituted prolines is a pertinent
approach to mimic functionalized natural ꢀ-turns of types I, II,
and II′ found in proteins.5
Several useful methods for the synthesis of 3-substituted
prolines are reported in the literature,6 and we have developed
a general approach based on the amino-zinc-ene-enolate cy-
clization (AZEE cyclization).7,8 We report here the application
of this methodology to the preparation of proline-homotryp-
tophane chimeras suitably protected for peptide synthesis.
Proline chimeras are tools combining amino acids side-chain
functionalities with conformational rigidity of pyrrolidine ring.1
One can distinguish between four classes of proline chimeras,
depending on the position of the pyrrolidine ring on which the
side-chain functionality is introduced. Among these chimeras,
3-substituted prolines are valuable tools for medicinal chemistry
first and biological applications. For example, in SAR studies
of biologically active peptides, these proline analogues have
been used to replace native residues with the aim of probing
both the information brought by the side chain and the
conformation (around the peptide backbone and the side chain)
of the native residue.2 cis-3-Substituted prolines have also been
used to build functionalized PPII helices (e.g., polyproline II
helix), allowing the development of protein-protein interaction
inhibitors.3 In the same manner, if the insertion of proline in a
heterochiral sequence remains the easiest strategy to induce a
Results and Discussion
The AZEE cyclization is a straightforward method for the
synthesis of cis-3-substituted prolines. The versatility of this
(3) Jacquot, Y.; Broutin, I.; Miclet, E.; Nicaise, M.; Gouasdoue, N.; Joss,
C.; Karoyan, P.; Desmadril, M.; Ducruix, A.; Lavielle, S. Bioorg. Med. Chem.
2007, 15, 1439.
(4) Chalmers, D. K.; Marshall, G. R. J. Am. Chem. Soc. 1995, 117, 5927.
(5) Quancard, J.; Karoyan, P.; Lequin, O.; Wenger, E.; Aubry, A.; Lavielle,
S.; Chassaing, G. Tetrahedron Lett. 2004, 45, 623.
(6) (a) Kumar, S.; Wang, Q.; Sasaki, N. A. Tetrahedron 2007, 63, 2084. (b)
Angle, S. R.; Belanger, D. S. J. Org. Chem. 2004, 69, 4361, and references
therein.
† UPMC Univ Paris 06, UMR 7613 and FR2769.
‡ CNRS, UMR 7613 and FR2769.
§ Genzyme Pharmaceuticals.
(1) For a review on proline chimeras regarding syntheses, structural features,
and biological applications, see: Karoyan, P.; Sagan, S.; Lequin, O.; Quancard,
J.; Lavielle, S.; Chassaing, G. Targets Heterocycl. Syst. 2004, 8, 216.
(2) (a) Sagan, S.; Quancard, J.; Lequin, O.; Karoyan, P.; Chassaing, G.;
Lavielle, S. Chem. Biol. 2005, 12, 5–555. (b) Sugase, K.; Horikawa, M.;
Sugiyama, M.; Ishiguro, M. J. Med. Chem. 2004, 47, 489.
(7) For the synthesis of 3-substituted prolines through amino-zinc-ene-enolate
cyclization, see: Quancard, J.; Labonne, A.; Jacquot, Y.; Chassaing, G.; Lavielle,
S.; Karoyan, P. J. Org. Chem. 2004, 69, 7940, and references therein.
(8) For a review on carbometalation of unactivated alkenes by zinc enolate
derivatives, see: Pe´rez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F.
New.J. Chem. 2008, 32, 594, and references therein.
6706 J. Org. Chem. 2008, 73, 6706–6710
10.1021/jo801006a CCC: $40.75 2008 American Chemical Society
Published on Web 07/26/2008

Amino-Zinc-Ene-Enolate Cyclization
SCHEME 1. Negishi Cross-Coupling Reaction with Pd2(dba)3/P(o-Tolyl)3
SCHEME 2. ꢀ-Hydride Elimination
SCHEME 3. Iodation and Boc Protection of Indol Rings Followed by Negishi Coupling
strategy is linked to the relative stability of zinc intermediate
that can be transmetalated into a variety of new organometallic
species, allowing reaction pathways not available for the zinc
derivative.9 We recently took advantage of this characteristic
to achieve Pd(0) Negishi cross-coupling reactions10 of the cyclic
zinc intermediate with iodo-benzene for the preparation of
proline-phenylalanine chimeras. This cross-coupling was suc-
cessful using in situ generated Pd(0) from Pd2(dba)3 and tri-o-
tolylphosphine.11 However, these conditions failed for coupling
indole rings. In that case, the formation of the exo-3-methylene-
prolinate 4 and the reduced indole ring 5 was observed together
with the hydrolysis product 3, whatever the protecting group
on the indole nitrogen (Scheme 1).
alkyl ligands on Pd12 (Scheme 2). This ꢀ-hydride elimination,
competing with the reductive elimination, was not observed
through coupling of aryl-iodide to zinc intermediate [2].
To avoid this side reaction, the use of Pd catalysts derived
from Buchwald’s Ru-phos, Hartwig’s Q-phos and Fu’s [(t-
Bu3PH)]-BF4 have been reported in the R-arylation of N-Boc-
pyrrolidine via transmetalation/Negishi coupling.13 Fu’s catalyst
was chosen for reasons of cost, availability, and ease of use,
and thus we considered the coupling of indole rings using this
air-stable trialkylphosphonium salt14 as described in Scheme 3
and Table 1.
The zinc intermediate [2] was generated starting from the
commercially available olefin 1.15 Carbocyclization was per-
formed after the deprotonation/transmetalation sequence (Scheme
This observation can be explained by considering the rapid
ꢀ-hydride elimination that has been reported with secondary
(12) Heck, R. F. Acc. Chem. Res. 1979, 12, 146.
(9) Knochel, P.; Perea, J. J. A.; Jones, P. Tetrahedron 1998, 54, 8275.
(10) Negishi, E. Acc. Chem. Res. 1982, 15, 340.
(11) Quancard, J.; Magellan, H.; Lavielle, S.; Chassaing, G.; Karoyan, P.
Tetrahedron Lett. 2004, 45, 2185.
(13) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen, C.
J. Am. Chem. Soc. 2006, 128, 3538.
(14) Netherton, M.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(15) Genzyme Pharmaceuticals, Eichenweg 1, CH-4410 Liestal, Switzerland.
J. Org. Chem. Vol. 73, No. 17, 2008 6707

Mothes et al.
TABLE 1. Yields of Iodation, Boc Protection, and Negishi Coupling of Indol Rings
SCHEME 4. Synthesis of Enantiomer 9a′
3). The cis-stereochemistry observed during the cyclization
process of the linear R-amino-ester 1 was initially attributed to
a chair-like transition state involving O-metalated species.16
Recent studies realized by Chemla and co-workers concluded
that C-metalated species explain the stereochemistry observed
in carbocyclizations involving zinc-enolates.17 Anyway, the
absolute configurations of both chiral centers created during the
cyclization process depend on the chiral auxiliary used in this
reaction, (S)-R-methyl-benzylamine, leading to cis-3-substituted
proline derivatives with a 2S absolute configuration. The cross-
coupling reaction was realized at room temperature, with first
iodo-indole 8a prepared by direct iodination of compounds 6a
followed by Boc-protection of the indole nitrogen.18 Boc
protection was required to achieve the cross-coupling reaction.
Only trace amounts of cross-coupling product were observed
with unprotected indole 7a, the major compound being the
hydrolysis product 3, and no reaction occurred with N-benzyl-
protected indole (not reported in Scheme 3 and Table 1). These
results may be linked to the electron-withdrawing character of
the N-Boc group, which favors the oxidative addition step of
the palladium catalyst into the indoyl-iodine bond and thus
favors the overall catalytic process. Compound 9a was obtained
with good yields after isolation and purification by flash column
chromatography. N-Boc-protected indoles 8b-e were prepared
using the same procedure. These indoles were engaged in the
cross-coupling reaction leading to compounds 9b-e with good
to low yields. The lower yields may be explained by considering
that if electron-withdrawing character of the N-Boc group favors
the oxidative addition step, electron-withdrawing groups on the
aromatic ring might disfavor the reductive elimination process
leading to the cross-coupling products; a balance between
electron-donating or -withdrawing effects is required to achieve
the reaction with satisfactory yields.
The same procedure was used to prepare compound 9a′, the
enantiomer of compound 9a, starting from the commercially
available linear R-amino ester 1′ (Scheme 4).
The prolino-homotryptophane chimera 9a′ was obtained with
satisfactory yields, as for its enantiomer 9a. Finally, both
enantiomers (9a and 9a′) were debenzylated by catalytic
hydrogenation over palladium charcoal (Scheme 5). The or-
thogonally protected compounds 10 and 10′ were obtained after
Fmoc protection of the pyrrolidine ring nitrogen.
In conclusion, the syntheses of cis-3-substituted prolino-
homotryptophane chimeras were considered via AZEE cycliza-
tion and Negishi cross-coupling reaction. Despite the failure of
classical Pd catalyst for Negishi cross-coupling reaction, Fu’s
catalyst allowed the introduction of indoles rings on the
pyrrolidine cycle. Orthogonally protected and optically pure
(16) (a) Karoyan, P.; Chassaing, G. Tetrahedron Lett. 1997, 38, 85. (b)
Karoyan, P.; Quancard, J.; Vaissermann, J.; Chassaing, G. J. Org. Chem. 2003,
68, 2256.
(17) Sliwinski, E.; Prian, F.; Denes, F.; Chemla, F.; Normant, J.-F. C. R.
Chim. 2003, 6, 67, and ref 8.
(18) Witulski, B.; Buschmann, N.; Bergstra¨sser, U. Tetrahedron 2000, 56,
8473.
6708 J. Org. Chem. Vol. 73, No. 17, 2008

Amino-Zinc-Ene-Enolate Cyclization
SCHEME 5. Orthogonally Protected
Prolino-homotryptophanes Derivatives
was obtained after the usual workup and purification by flash
chromatography (cyclohexane/ethyl acetate 9:1). [R]20 -34.7 (c
D
1, CHCl3). 1H NMR (250 MHz, CDCl3) δ: 8.28 (m, 1H), 8.18 (m,
2H), 7.40-7.22 (m, 11H), 5.12 (AB, 2H, J ) 12.2 Hz), 3.78 (q,
1H, J ) 6.8 Hz), 3.56 (d, 1H, J ) 7.5 Hz), 3.12 (m, 1H), 2.95 (m,
1H), 2.81-2.71 (m, 2H), 2.39 (m, 1H), 1.92 (m, 1H), 1.76 (m,
1H), 1.75 and 1.66 (2s, 9H, Boc cis/trans isomerization), 1.36 (d,
3H, J ) 6.8 Hz). 13C NMR (250 MHz, CDCl3) δ: 172.8, 148.9,
144.3, 143.4, 138.6, 135.7, 130.4, 128.8, 128.6, 128.4, 127.4, 127.2,
125.6, 120.0, 119.7, 115.4, 115.3, 84.9, 66.4, 66.0, 61.4, 49.8, 41.6,
30.1, 28.2, 26.1, 22.9. HRMS calcd for C34H37N3O6 [MH+]:
584.2755. Found: 584.2764.
tert-Butyl 3-(((2S,3R)-2-(Benzyloxycarbonyl)-1-((S)-1-phenyleth-
yl)pyrrolidin-3-yl)methyl)-5-chloro-1H-indole-1-carboxylate 9d.
Same protocol as for 9a: LDA (2 mL, 4 mmol), (S)-benzyl 2-(but-
3-enyl(1-phenylethyl)amino)acetate 1 (647 mg, 2 mmol), THF 51
mL), ZnBr2 (1 M, 6 mL), tert-butyl-5-chloro-3-iodo-1H-indole-1-
carboxylate 8d (831 mg, 2.2 mmol), Pd(OAc)2 (18 mg, 80 µmol),
and tBu3P-HBF4 (29 mg, 100 µmol). A yellow oil (495 mg, 43%)
was obtained after the usual workup and purification by flash
compounds were obtained, and their use in SAR studies of
biologically active peptides is currently underway.
Experimental Section
tert-Butyl 3-(((2S,3R)-2-(Benzyloxycarbonyl)-1-((S)-1-phenyleth-
yl)pyrrolidin-3-yl)methyl)-1H-indole-1-carboxylate 9a. LDA (12
mL, 24 mmol) was added at -78 °C to a solution of (S)-benzyl
2-(but-3-enyl(1-phenylethyl)amino)acetate 1 (6.47 g, 20 mmol) in
dry THF (30 mL) under argon. ZnBr2 (1.2 M in Et2O, 50 mL) was
then added at the same temperature. The reaction mixture was stirred
overnight at room temperature under argon. tert-Butyl 3-iodo-1H-
indole-1-carboxylate 8a (8.92 g, 26 mmol) in dry THF (10 mL),
Pd(OAc)2 (180 mg, 0.80 mmol), and tBu3P-HBF4 (290 mg, 1.0
mmol) were then successively added, and the mixture was stirred
overnight at room temperature under argon. Et2O was added, and
the organic layer was washed with NH4Cl, dried over MgSO4, and
concenterd in vacuo. The residue was purified by flash chroma-
tography (cyclohexane/ethyl acetate 95:5) to give a yellow oil (6.45
g, 60%). [R]20D -37.9 (c 1, CHCl3). 1H NMR (250 MHz, CDCl3)
δ: 8.09 (d, 1H, J ) 8.0 Hz), 7.38-7.16 (m, 14H), 5.10 (AB, 2H,
J ) 12 Hz), 3.73 (q, 1H, J ) 6.8 Hz), 3.55 (d, 1H, J ) 7.7 Hz),
3.09 (m, 1H), 2.91 (m, 1H), 2.81-2.73 (m, 2H), 2.36 (m, 1H),
1.92 (m, 1H), 1.76 (m, 1H), 1.64 (s, 9H), 1.35 (d, 3H, J ) 6.8 Hz).
13C NMR (250 MHz, CDCl3) δ: 173.2, 149.8, 144.5, 135.9, 135.5,
130.5, 128.9, 128.6, 128.4, 127.5, 127.2, 124.4, 122.8, 122.4, 119.0,
115.3, 83.5, 66.7, 66.0, 61.6, 50.1, 41.8, 30.2, 28.3, 26.4, 22.9.
HRMS calcd for C34H38N2O4 [MH+]: 539.2904. Found: 539.2910.
tert-Butyl 3-(((2S,3R)-2-(Benzyloxycarbonyl)-1-((S)-1-phenyleth-
yl)pyrrolidin-3-yl)methyl)-5-methoxy-1H-indole-1-carboxylate 9b.
Same protocol as for 9a: LDA (2 mL, 4 mmol), (S)-benzyl 2-(but-
3-enyl(1-phenylethyl)amino)acetate 1 (647 mg, 2 mmol), THF (5
mL), ZnBr2 (1 M, 6 mL), tert-butyl 3-iodo-5-methoxy-1H-indole-
1-carboxylate 8b (821 mg, 2.2 mmol), Pd(OAc)2 (18 mg, 80 µmol),
and tBu3P-HBF4 (29 mg, 100 µmol). A yellow oil (593 mg, 52%)
was obtained after the usual workup and purification by flash
chromatography (cyclohexane/ethyl acetate 9:1). [R]20 -35.2 (c
D
1
1, CHCl3). H NMR (250 MHz, CDCl3) δ: 8.03 (d, 1H, J ) 8.5
Hz), 7.36-7.25 (m, 13H), 5.16 (AB, 2H, J ) 12.2 Hz), 3.77 (q,
1H, J ) 6.5 Hz), 3.57 (d, 1H, J ) 7.5 Hz), 3.13 (m, 1H), 2.97 (m,
1H), 2.84-2.67 (m, 2H), 2.31 (m, 1H), 1.96 (m, 1H), 1.77 (m,
1H), 1.76 and 1.66 (2s, 9H, Boc cis/trans isomerization), 1.38 (d,
3H, J ) 6.5 Hz). 13C NMR (250 MHz, CDCl3) δ: 173.0 149.4,
144.4, 135.8, 133.8, 131.7, 128.9, 128.6, 128.5, 128.4, 128.1, 127.5,
127.2, 124.5, 124.0, 118.6, 118.5, 116.3, 83.8, 66.5, 66.0, 61.5,
49.9, 41.6, 30.1, 28.2, 26.2, 22.9. HRMS calcd for C34H37ClN2O4
[MH+]: 573.2515. Found: 573.2524.
1-tert-Butyl 6-Methyl 3-(((2S,3R)-2-(Benzyloxycarbonyl)-1-((S)-
1-phenylethyl)pyrrolidin-3-yl)methyl)-1H-indole-1,6-dicarboxy-
late 9e. Same protocol as for 9a: LDA (500 µL, 1 mmol), (S)-
benzyl 2-(but-3-enyl(1-phenylethyl)amino)acetate 1 (162 mg, 0.5
mmol), THF (1 mL), ZnBr2 (1 M, 1.5 mL), 1-tert-butyl-6-methyl-
3-iodo-1H-indole-1,6-dicarboxylate 8e (241 mg, 0.60 mmol),
Pd(OAc)2 (4 mg, 20 µmol), and tBu3P-HBF4 (7 mg, 30 µmol). A
yellow oil (70 mg, 23%) was obtained after the usual workup and
purification by flash chromatography (cyclohexane/ethyl acetate
1
9:1). [R]20 -23.4 (c 1, CHCl3). H NMR (250 MHz, CDCl3) δ:
D
8.82 (s, 1H), 7.89 (dd, 1H, J ) 8.5 Hz, J ) 1.5 Hz), 7.43-7.22
(m, 12H), 5.11 (AB, 2H, J ) 12 Hz), 3.94 (s, 3H), 3.74 (q, 1H, J
) 6.5 Hz), 3.55 (d, 1H, J ) 7.5 Hz), 3.11 (m, 1H), 2.94 (m, 1H),
2.79-2.73 (m, 2H), 2.37 (m, 1H), 1.92 (m, 1H), 1.80 (m, 1H),
1.79 and 1.67 (2s, 9H, Boc cis/trans isomerization), 1.36 (d, 3H, J
) 6.5 Hz). 13C NMR (250 MHz, CDCl3, Boc cis/trans isomeriza-
tion) δ: 173.0, 167.7, 149.3, 144.3, 135.8, 134.9, 134.1, 128.8,
128.6, 128.4, 127.5, 127.2, 126.0, 125.8, 125.7, 123.6, 123.5, 119.1,
118.7, 117.2, 84.1, 66.6, 66.5, 66.0, 61.6, 61.4, 52.2, 52.0, 49.9,
41.7, 30.1, 28.3, 28.1, 26.2, 22.9, 22.8. HRMS calcd for C36H40N2O6
[MH+]: 597.2959. Found: 597.2969.
chromatography (cyclohexane/ethyl acetate 9:1). [R]20 -35.3 (c
D
1
1, CHCl3). H NMR (250 MHz, CDCl3) δ: 8.01 (d, 1H, J ) 9.0
Hz), 7.35-7.25 (m, 11H), 6.93 (dd, 1H, J ) 9.0 Hz, J ) 2.5 Hz),
6.88 (d, 1H, J ) 2.5 Hz), 5.13 (AB, 2H, J ) 12,D Hz), 3.86 (s,
3H), 3.77 (q, 1H, J ) 6.8 Hz), 3.59 (d, 1H, J ) 7.5 Hz), 3.13 (m,
1H), 2.95 (m, 1H), 2.85-2.75 (m, 2H), 2.38 (m, 1H), 1.96 (m,
1H), 1.82 (m, 1H), 1.66 (s, 9H), 1.39 (d, 3H, J ) 6.8 Hz). 13C
NMR (250 MHz, CDCl3, Boc cis/trans isomerization) δ: 173.1,
155.7, 149.7, 144.3, 135.8, 131.3, 130.2, 128.8, 128.5, 128.4, 128.0,
127.5, 127.1, 123.5, 118.9, 116.0, 115.9, 112.7, 101.9, 83.2, 66.7,
66.6, 66.0, 61.6, 61.4, 55.9, 55.7, 50.0, 41.7, 30.2, 28.3, 28.2, 26.4,
22.9, 22.8. HRMS calcd for C35H40N2O5 [MH+]: 569.3010. Found:
569.3018.
tert-Butyl 3-(((2R,3S)-2-(Benzyloxycarbonyl)-1-((R)-1-phenyleth-
yl)pyrrolidin-3-yl)methyl)-1H-indole-1-carboxylate 9a′. Same pro-
tocol as for 9a starting from (R)-benzyl 2-(but-3-enyl(1-phenyl-
ethyl)amino)acetate 1′ yielding a yellow oil. [R]20 39.6° (c 1,
D
CHCl3). 1H NMR (250 MHz, CDCl3) δ: 8.09 (d, 1H, J ) 8.0 Hz),
7.38-7.16 (m, 14H), 5.10 (AB, 2H, J ) 12 Hz), 3.73 (q, 1H, J )
6.8 Hz), 3.55 (d, 1H, J ) 7.7 Hz), 3.09 (m, 1H), 2.91 (m, 1H),
2.81-2.73 (m, 2H), 2.36 (m, 1H), 1.92 (m, 1H), 1.76 (m, 1H),
1.64 (s, 9H), 1.35 (d, 3H, J ) 6.8 Hz). 13C NMR (250 MHz, CDCl3)
δ: 173.2, 149.8, 144.5, 135.9, 135.5, 130.5, 128.9, 128.6, 128.4,
127.5, 127.2, 124.4, 122.8, 122.4, 119.0, 115.3, 83.5, 66.7, 66.0,
61.6, 50.1, 41.8, 30.2, 28.3, 26.4, 22.9. HRMS calcd for C34H38N2O4
[MH+]: 539.2904. Found: 539.2911.
tert-Butyl 3-(((2S,3R)-2-(Benzyloxycarbonyl)-1-((S)-1-phenyleth-
yl)pyrrolidin-3-yl)methyl)-5-nitro-1H-indole-1-carboxylate 9c.
Same protocol as for 9a: LDA (2 mL, 4 mmol), (S)-benzyl 2-(but-
3-enyl(1-phenylethyl)amino)acetate 1 (647 mg, 2 mmol), THF (5
mL), ZnBr2 (1 M, 6 mL), tert-butyl 3-iodo-5-nitro-1H-indole-1-
carboxylate 8c (854 mg, 2.2 mmol), Pd(OAc)2 (18 mg, 80 µmol),
and tBu3P-HBF4 (29 mg, 100 µmol). A yellow oil (412 mg, 35%)
(2S,3R)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-3-((1-(tert-bu-
toxycarbonyl)-1H-indol-3-yl)methyl)pyrrolidine-2-carboxylic Acid
10. A mixture of compound 9a (6.25 g, 11.6 mmol) and 10% Pd/C
(1.16 g) in MeOH (58 mL) was stirred for 90 h under 5 bar
J. Org. Chem. Vol. 73, No. 17, 2008 6709

Mothes et al.
hydrogen. After filtration over a Celite pad, the solvent was
concentrated. A white powder, (2S,3R)-3-((1-(tert-butoxycarbonyl)-
1H-indol-3-yl)methyl)pyrrolidine-2-carboxylic acid (2.60 g, 73%),
was obtained after crystallization from Et2O/pentane.
(2R,3S)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-3-((1-(tert-bu-
toxycarbonyl)-1H-indol-3-yl)methyl)pyrrolidine-2-carboxylic Acid
10′. Same protocol as for 10 starting from 9a′ yielding a white
powder. Mp, degradation over 90 °C, [R]20 -11.0 (c 1, CHCl3).
D
1H NMR (250 MHz, CDCl3) δ: 8.13 (d, 1H, J ) 8.0 Hz), 7.77-7.06
(m, 12H), 4.59-4.12 (m, 4H), 3.76 (m, 1H), 3.40 (m, 1H), 3.08
(m, 1H), 2.82 (m, 1H), 2.54 (m, 1H), 1.96 (m, 2H), 1.67 and 1.58
(2s, 9H, Fmoc and Boc cis/trans isomerization). 13C NMR (250
MHz, CDCl3, Fmoc and Boc cis/trans isomerization) δ: 176.0,
175.5, 155.3, 154.5, 149.8, 144.1, 143.9, 143.8, 141.4, 135.5, 130.3,
127.8, 127.2, 125.3, 124.6, 123.3, 122.6, 120.1, 118.9, 118.3, 118.2,
115.5, 115.0, 83.8, 67.9, 62.5, 62.1, 47.2, 46.4, 46.1, 42.9, 41.8,
30.2, 28.6, 28.4, 25.4. HRMS calcd for C34H34N2O6 [MNa+]:
589.2309. Found: 589.2319.
(2S,3R)-3-((1-(tert-Butoxycarbonyl)-1H-indol-3-yl)methyl)pyr-
rolidine-2-carboxylic acid (1.12 g, 3.25 mmol) was dissolved in
30 mL of water and in 30 mL of dioxane. FmocOSu (1.32 g, 3.9
mmol) was slowly added, and then K2CO3 (7.15 g, 7.15 mmol)
was added. The solution was stirred overnight at room temper-
ature. The solvent was evaporated, and the residue was taken
up in water. The aqueous layers were extracted three times with
ethyl acetate. The combined organic layers were dried over
MgSO4 and concentrated. A white powder (1.43 g, 78%) was
obtained after purification by flash chromatography (CH2Cl2/MeOH/
acetic acid, 95:5:0.1). Mp, degradation over 90 °C. [R]20D 7.8 (c 1,
CHCl3). 1H NMR (250 MHz, CDCl3) δ: 8.13 (d, 1H, J ) 8.0 Hz),
7.77-7.06 (m, 12H), 4.59-4.12 (m, 4H), 3.76 (m, 1H), 3.40 (m,
1H), 3.08 (m, 1H), 2.82 (m, 1H), 2.54 (m, 1H), 1.96 (m, 2H), 1.67
and 1.58 (2s, 9H, Fmoc and Boc cis/trans isomerization). 13C NMR
(250 MHz, CDCl3, Fmoc and Boc cis/trans isomerization) δ: 176.0,
175.5, 155.3, 154.5, 149.8, 144.1, 143.9, 143.8, 141.4, 135.5, 130.3,
127.8, 127.2, 125.3, 124.6, 123.3, 122.6, 120.1, 118.9, 118.3, 118.2,
115.5, 115.0, 83.8, 67.9, 62.5, 62.1, 47.2, 46.4, 46.1, 42.9, 41.8,
30.2, 28.6, 28.4, 25.4. HRMS calcd for C34H34N2O6 [MNa+]:
589.2309. Found: 589.2319.
Acknowledgment. C.M. is grateful to Genzyme Pharma-
ceutilcals for financial support of her Ph.D. P.K. thanks Jean-
Claude Tabet and his team for the HRMS analysis.
Supporting Information Available: General considerations,
iodo-indoles syntheses, and NMR data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801006A
6710 J. Org. Chem. Vol. 73, No. 17, 2008