Synthesis of new perhydroindole derivatives and their evaluation in ruthenium-catalyzed hydrogen transfer reduction

Article abstract of DOI:10.1002/ejoc.200700476

New perhydroindole derivatives were synthesized with good yields and evaluated as chiral ligands in the Ru^II-catalyzed hydride transfer reduction of acetophenone. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700476

FULL PAPER
DOI: 10.1002/ejoc.200700476
Synthesis of New Perhydroindole Derivatives and Their Evaluation in
Ruthenium-Catalyzed Hydrogen Transfer Reduction
Benoît Liégault,[a] Xiaoping Tang,[a] Christian Bruneau,*[a] and Jean-Luc Renaud*[a]
Keywords: Perhydroindole / Proline / Hydride transfer / Ruthenium / Homogeneous catalysis
New perhydroindole derivatives were synthesized with good
yields and evaluated as chiral ligands in the RuII-catalyzed
hydride transfer reduction of acetophenone.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
ported on the related perhydroindole-based compounds. In
The development of new chiral ligands for catalytic the presence of perhydroindanylmethanol (1), diethylzinc
asymmetric transformations is one of the most important reacted with benzaldehyde to provide 1-phenylpropan-1-ol
issues in the search of efficient asymmetric syntheses.[1] Ni- with 90% ee,[11] and acetophenone was reduced by BH3
trogen-containing ligands are being used increasingly in with high ee.[12] Some perhydroindole derivatives were also
asymmetric catalysis. They turn out to be suitable for many used in enantioselective ring opening of meso-epoxides[13]
types of catalysis, especially for heterogeneous catalysis.[2] and desymmetrization of cyclic carbamates.[14] After dem-
In particular, much emphasis has been placed on the role onstrating the efficiency of perhydroindolic acid as an or-
of nitrogen-containing compounds in transition-metal ca- ganocatalyst in the aldol reaction,[15] we now report the
talysis. Chiral amino acid based ligands are of significant preparation of new perhydroindole amide derivatives 2–6
importance due to their ready availability, low cost, and (Figure 1) and the evaluation of their catalytic activities as
modular nature.
ligands in ketone reduction by hydride transfer. As the NH
In contrast to the proline derivatives, which have been function within the molecule is crucial to carry out the
used in enantioselective C=C bond hydrogenation,[3] hy- metal-catalyzed asymmetric reduction of prochiral
dride transfer,[4] cyclopropanation,[5] selective oxidation of ketones,[16] we synthesized the amino alcohol 1, the perhy-
sulfides to sulfoxides,[6] cyanosilylation,[7] aldol reaction and droindole amides 2,3 and the C2-symmetrical bis(perhydro-
organocatalytic transformations,[8–10] little has been re- indolic amides) 4–6 (Figure 1).
Figure 1. Perhydroindole derivatives 1–6.
[a] Sciences Chimiques de Rennes, UMR 6226, Catalyse et
Organométalliques, Université de Rennes 1
Results and Discussion
Campus de Beaulieu, 35042 Rennes Cedex, France
Fax: +33-22323-6939
Compounds 1–6 were prepared from the (S,S,S)-perhy-
droindolic acid 7, as outlined in Scheme 1.
E-mail: christian.bruneau@univ-rennes1.fr
jean-luc.renaud@univ-rennes1.fr
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 934–940

New Perhydroindole Derivatives
Scheme 1. Retrosynthesis of perhydroindole derivatives.
The amino alcohol 1 was prepared by reduction of the [3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochlo-
amino acid 7 using lithium aluminium hydride in diethyl ride (EDCI) and 4-(dimethylamino)pyridine (4-DMAP) led
ether in excellent yield (Scheme 2).[11,12]
to the bis(perhydroindolic amides) 10,11 in low to moderate
yields (Scheme 3).
From the protected amino amide 9 and bis(amino
amides) 10,11, the last step towards amides 2, 4, and 5 was
the removal of the protecting group from the indole nitro-
gen atom. The deprotection of these derivatives by hydro-
genolysis using Pd/C as the catalyst resulted either in no
reaction or in irreproducible reactions.
Scheme 2. Preparation of amino alcohol 1.
Thus, we envisioned an alternative protecting group
which would be easier to cleave and would be removed un-
der acidic conditions. The protection of the secondary
amine 7 using (Boc)2O was performed to provide 12 in 97%
yield. The diastereomerically pure amides 13 and 14 were
isolated in moderate to good yields using the Sanchez pro-
cedure,[17] whereas the bis(perhydroindolic amides) 15–17
were obtained in good yields using the peptide coupling
conditions previously described by Zhao (Scheme 4).[19]
The subsequent deprotection of the secondary amine de-
We next turned our attention to the synthesis of the
amides 2–6. The protection of the amine was first per-
formed using benzyl chloroformate to give 8 in 75% yield.
Amide 9 was then prepared according to the procedure de-
scribed by Sanchez et al.[17,18] An anhydride intermediate
was first prepared by reaction of 8 with ethyl chloroformate
in the presence of triethylamine in THF at 0 °C, and then
directly treated with a substoichiometric amount of sodium
amide at –78 °C to prevent epimerization, providing com-
pound 9 in a moderate 62% yield. Peptide coupling of the
protected amino acid 8 with ethylenediamine (en) or (S,S)- rivatives was performed in the presence of trifluoroacetic
diphenylethylenediamine [(S,S)-dpen] in the presence of 1- acid in dichloromethane at 0 °C.[20] The resulting amino
Scheme 3. Synthesis of Cbz-protected perhydroindole amide 9 and bis(perhydroindole amides) 10,11.
Eur. J. Org. Chem. 2008, 934–940
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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935

B. Liégault, X. Tang, C. Bruneau, J.-L. Renaud
FULL PAPER
Scheme 4. Synthesis of Boc-protected perhydroindolic amides 13,14 and bis(perhydroindolic amides) 15–17.
amides 2,3 and bis(amino amides) 4–6 were isolated in
quantitative yields (Scheme 5).
With ligands 1–7, we first screened different reaction
conditions using precatalyst [RuCl2(p-cymene)]2 and either
The potential of these new optically pure perhydroindole isopropyl alcohol/KOH or the azeotropic HCOOH/Et3N
derivatives was then evaluated by testing their efficiency as mixture as the hydride source for the transfer hydrogenation
ligands in the RuII-catalyzed hydride transfer reduction of (Table 1). The chiral ruthenium complexes were prepared in
ketones.
situ by heating a mixture of the ruthenium dimer and the
Enantioselective transfer hydrogenation of ketones with chiral ligand in refluxing isopropyl aclohol. Catalytic reac-
no functional neighboring group represents a very useful tions were carried out by adding acetophenone and either
method for the preparation of optically active alcohols.[21] KOH to the previous isopropyl alcohol/catalyst solution
Recently, Noyori and co-workers have shown that the NH (conditions A) or a mixture of HCOOH/Et3N to the cata-
function within the ligand molecule is crucial for the asym- lyst after removing isopropyl alcohol (conditions B). The
metric transformation of prochiral ketones into chiral mixture was allowed to react for a determined time, and
alcohols.[22] Among the ligands applied to this reaction, di- then it was filtered through Celite (conditions A) or
amines[21a] and amino alcohols[23] have led to high catalytic quenched with diluted HCl (conditions B).
activities and enantioselectivities. Proline amides have also
In the first attempt using isopropyl alcohol as hydride
been used and have shown potential.[4,18] In order to evalu- source with the amino alcohol 1 (conditions A), we isolated
ate the perhydroindole derivatives 1–7, we investigated the 1-phenylethan-1-ol in high yield and good enantiomeric ex-
hydride transfer reaction with acetophenone and compared cess (Table 1, Entry 1). Under similar reaction conditions,
the results to those obtained with proline amides.
the amino amides 2,3 did not provide any efficient catalysts
Scheme 5. Synthesis of perhydroindole derivatives 2–5.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 934–940

New Perhydroindole Derivatives
Table 1. Perhydroindole derivatives 1–7 as ligands in the hydride to good yields and reasonable enantioselectivities (Table 2).
transfer reaction with acetophenone.
The catalyst tolerated the presence of methoxy and halide
substituents on the ortho position of the phenyl ring.
Conclusions
En-
try gand
Li-
Condi-
tions[a]
Time
[h]
Yield [%][b]
ee [%][c]
Very efficient methods for the synthesis of amides 2,3
and C2-symmetrical bis(amides) 4–6 based on the (S,S,S)-
perhydroindole skeleton have been disclosed. These com-
pounds are the first members of a new class of perhydroin-
dole compounds with potential properties as polydentate
nitrogen ligands. They have been evaluated in the asymmet-
ric transfer hydrogenation of ortho-substituted acetophe-
none (up to 62% ee). These C1- and C2-symmetrical aza
derivatives provided encouraging results and will be tested
in other enantioselective reactions.
1
2
3
4
5
6
7
8
1
1
2
2
3
3
4
5
A
B
A
BЈ
A
BЈ
AЈ
AЈ
16
16
16
20
16
20
48
48
99
n.r.[d]
n.r.[d]
32
60
–
–
10
–
50
52
62
n.r.[d]
40
60
low yield
[a] A: acetophenone/KOH/L*/Ru, 100:5:2:1, iPrOH, room temp.,
16 h. AЈ: acetophenone/KOH/L*/Ru, 100:5:2:1, iPrOH, room
temp., 48 h. B: acetophenone/L*/Ru, 100:2:1, HCOOH/NEt3, 5:2,
room temp., 16 h. BЈ: acetophenone/L*/Ru, 100:2:1, HCOOH/
NEt3, 5:2, 45 °C, 20 h. [b] Isolated yield. [c] Determined by HPLC
analysis, with Chiralcel OD-H chiral columns [(S) enantiomer as
major product], after purification by flash chromatography. [d] No
reaction.
Experimental Section
General Remarks: Most experiments were carried out under argon.
1
Solvents were dried and purified in the usual manner. H and 13C
NMR spectra were recorded with Bruker Avance 200- or 300-DPX
spectrometers. Chemical shifts are given in ppm, referenced to the
residual proton resonance of the solvent. 13C NMR multiplicity is
reported with respect to proton (deduced from DEPT experiments;
s, quaternary C; d, CH; t, CH2; q, CH3). High resolution mass
spectra with electronic impact (HRMS-EI) or electrospray ioniza-
tion (MS-ESI) were obtained with a Varian Mat 311 or a Micro-
mass MS/MS ZABSpec TOF, respectively. TLC was performed on
Merck 60F254 silica gel plates, and all compounds were purified by
flash chromatography with Merck Si 60 silica gel (40–63 µm).
HPLC analyses were carried out with a Waters 1515 chromato-
graph equipped with a Waters 2487 UV detector, using Daicel Chi-
ralpack AS or Chiralcel OD-H chiral columns.
(Entries 3 and 5), which contrasts with the results obtained
with proline amide ligands.[4c] On the other hand, the bis-
(amino amide) 4 furnished the alcohol in moderate yield
(60%) and ee (52%) (Entry 7).
We next investigated the hydride transfer reaction in the
HCOOH/Et3N mixture (conditions B). The best result in
terms of reactivity and enantioselectivity was obtained with
ligand 3 (40% yield, 50% ee) (Table 1, Entry 6). However,
this result is worse than the one obtained with the amino
alcohol 1 in iPrOH in the presence of potassium hydroxide.
Thus, we decided to use ligand 1 to extend this reaction
to several aromatic ketones (Table 2).
(2S,3aS,7aS)-Octahydro-1H-indole-2-carboxamide (2): To a solu-
tion of amide 13 (134 mg, 0.5 mmol) in CH2Cl2 (5 mL) at 0 °C was
added TFA (2.5 mL). After 4 h at 0 °C, CH2Cl2 and TFA were
removed under reduced pressure, and the crude material was puri-
fied by flash chromatography (CH2Cl2/MeOH) to afford 84 mg
Table 2. (S,S,S)-Perhydroindolylmethanol 1 as ligand in the hydride
transfer reaction with aromatic ketones.[a]
1
(100%) of 2 as a white solid. H NMR (200 MHz, CD3OD): δ =
3.89 (dd, J = 9.1, 7.2 Hz, 1 H), 3.29 (m, 1 H), 2.30–1.95 (m, 2 H),
1.75–1.10 (m, 9 H) ppm. HRMS-EI: calcd. 124.11262 [M –
CONH2]+; found 124.1122.
(2S,3aS,7aS)-N-Phenyloctahydro-1H-indole-2-carboxamide (3):
Compound 14 was subjected to the same procedure that produced
1
compound 2 to yield 3 (100%). H NMR (200 MHz, CD3OD): δ
Entry
R
Yield [%][b]
ee [%][c]
= 7.63 (d, J = 8.1 Hz, 2 H), 7.35 (dd, J = 8.1, 7.4 Hz, 2 H), 7.15
(t, J = 7.4 Hz, 1 H), 4.51 (dd, apparent t, J = 8.5 Hz, 1 H), 3.80
(dt, J = 8.6, 5.6 Hz, 1 H), 2.63–2.42 (m, 2 H), 2.23–2.18 (m, 1 H),
2.05–1.88 (m, 1 H), 1.82–1.60 (m, 4 H), 1.54–1.36 (m, 3 H) ppm.
13C NMR (50 MHz, CD3OD): δ = 167.4 (s), 138.2 (s), 129.0 (d),
124.9 (d), 120.3 (d), 59.8 (d), 59.6 (d), 37.9 (d), 33.1 (t), 25.1 (t),
24.8 (t), 22.5 (t), 20.8 (t) ppm.
1
2
3
4
H
F
Cl
99
33
55
84
60
57
40
40
OMe
[a] Conditions: ketone/KOH/1/Ru, 100:5:2:1, iPrOH, room temp.,
16 h. [b] Isolated yield. [c] Determined by HPLC analysis, with
Chiralcel OD-H chiral columns [(S) enantiomer as major product],
after purification by flash chromatography.
(2S,2ЈS,3aS,3aЈS,7aS,7aЈS)-N,NЈ-(Ethane-1,2-diyl)bis(octahydro-
1H-indole-2-carboxamide) (4): Compound 15 was subjected to the
1
same procedure that produced compound 2 to yield 4 (100%). H
The scope of the hydride transfer reaction catalyzed by
ruthenium complex/1 in the presence of KOH in isopropyl
NMR (300 MHz, CDCl3): δ = 4.33 (dd, apparent t, J = 8.6 Hz, 2
H), 3.80 (dt, J = 8.9, 5.5 Hz, 2 H), 3.44 (ddd, J = 18.7, 11.4, 2.4 Hz,
alcohol with 1Ј-substituted aromatic ketones gave moderate 4 H), 2.54–2.39 (m, 4 H), 2.13–2.0 (m, 2 H), 2.0–1.89 (m, 2 H),
Eur. J. Org. Chem. 2008, 934–940
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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937

B. Liégault, X. Tang, C. Bruneau, J.-L. Renaud
FULL PAPER
1.78–1.57 (m, 8 H), 1.54–1.36 (m, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.2 (s), 59.2 (d), 58.6 (d), 39.1 (t), 37.5 (d), 32.4 (t),
24.7 (t), 24.3 (t), 22.0 (t), 20.4 (t) ppm. HRMS-ESI: calcd. 363.2760
[M + H]+; found 363.2762.
4.27 (m, 1 H), 3.92 (m, 1 H), 2.30–1.85 (m, 4 H), 1.75–1.10 (m, 7
H) ppm.
(2S,2ЈS,3aS,3aЈS,7aS,7aЈS)-Dibenzyl 2,2Ј-[Ethane-1,2-diylbis(az-
anediyl)]bis(oxomethylene)bis(octahydro-1H-indole-1-carboxylate)
(10): To a solution of amino acid 8 (1.3 g, 4.3 mmol), EDCI (1.23 g,
6.4 mmol, 1.5 equiv.) and DMAP (52 mg, 0.43 mmol, 0.1 equiv.) in
a mixture of CH2Cl2 (50 mL) and THF (15 mL) was added ethyl-
enediamine (170 µL, 2.6 mmol, 0.6 equiv.). After 16 h at room
temp., the reaction was quenched by addition of H2O and the mix-
ture extracted with CH2Cl2. The combined organic layers were
washed with brine, dried with MgSO4, filtered, and concentrated
under reduced pressure. The crude material was purified by flash
chromatography (heptane/EtOAc, 60:40) to afford 10 (600 mg,
(2S,2ЈS,3aS,3aЈS,7aS,7aЈS)-N,NЈ-[(1S,2S)-1,2-Diphenylethane-1,2-
diyl]bis(octahydro-1H-indole-2-carboxamide) (5): Compound 16
was subjected to the same procedure that produced compound 2
1
to yield 5 (100%). H NMR (300 MHz, CDCl3): δ = 7.52 (d, J =
7.4 Hz, 4 H), 7.40–7.27 (m, 6 H), 5.91 (apparent s, 2 H), 4.44 (dd,
apparent t, J = 8.7 Hz, 2 H), 3.62 (m, 2 H), 2.36–2.17 (m, 4 H),
1.80–1.70 (m, 2 H), 1.65–1.46 (m, 4 H), 1.44–1.22 (m, 12 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 168.6 (s), 138.6 (s), 128.1 (d),
127.2 (d), 126.5 (d), 59.2 (d), 58.5 (d), 57.2 (d), 37.2 (d), 32.4 (t),
24.4 (t), 24.0 (t), 22.0 (t), 20.1 (t) ppm. HRMS-EI: calcd. 514.33078
[M+]; found 514.3300.
1
64%) as a white solid. H NMR (300 MHz, CDCl3): δ = 7.51 (m,
2 H), 7.40–7.30 (m, 10 H), 5.11 (dd, J = 17.4, 12.6 Hz, 4 H), 4.18
(m, 2 H), 3.84 (m, 2 H), 3.53 (m, 2 H), 3.21 (m, 2 H), 2.30–2.20
(m, 4 H), 2.10–1.95 (m, 4 H), 1.90–1.10 (m, 14 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 173.7 (s), 155.4 (s), 137.1 (s), 128.9 (d), 128.4
(d), 128.2 (d), 67.4 (t), 61.7 (d), 58.2 (d), 38.0 (t), 37.4 (d), 31.7 (t),
28.3 (t), 26.3 (t), 24.2 (t), 20.8 (t) ppm.
(2S,2ЈS,3aS,3aЈS,7aS,7aЈS)-N,NЈ-[(1R,2R)-1,2-Diphenylethane-1,2-
diyl]bis(octahydro-1H-indole-2-carboxamide) (6): Compound 17
was subjected to the same procedure that produced compound 2
1
to yield 6 (100%). H NMR (300 MHz, CDCl3): δ = 7.52 (d, J =
7.4 Hz, 4 H), 7.40–7.27 (m, 6 H), 5.91 (apparent s, 2 H), 4.44 (dd,
apparent t, J = 8.7 Hz, 2 H), 3.62 (m, 2 H), 2.36–2.17 (m, 4 H),
1.80–1.70 (m, 2 H), 1.65–1.46 (m, 4 H), 1.44–1.22 (m, 12 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 168.6 (s), 138.6 (s), 128.1 (d),
127.2 (d), 126.5 (d), 59.2 (d), 58.5 (d), 57.2 (d), 37.2 (d), 32.4 (t),
24.4 (t), 24.0 (t), 22.0 (t), 20.1 (t) ppm. HRMS-EI: calcd. 514.33078
[M+]; found 514.3305.
(2S,2ЈS,3aS,3aЈS,7aS,7aЈS)-Dibenzyl 2,2Ј-[(1S,2S)-1,2-Diphenyl-
ethane-1,2-diyl]bis(azanediyl)bis(oxomethylene)bis(octahydro-1H-in-
dole-1-carboxylate) (11): The same procedure was applied as for
compound 10, replacing ethylenediamine by (S,S)-diphenylethy-
1
lenediamine to yield 11 (15%). H NMR (200 MHz, CDCl3): δ =
7.38–7.22 (m, 20 H), 5.26 (m, 2 H), 5.09 (m, 2 H), 4.36–4.24 (m, 4
H), 3.95 (m, 2 H), 2.30–1.85 (m, 8 H), 1.70–1.10 (m, 14 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 142.5 (s), 140.8 (s), 129.0 (d),
128.9 (d), 128.8 (d), 128.4 (d), 128.2 (d), 127.9 (d), 127.7 (d), 127.1
(d), 126.9 (d), 67.5 (t), 60.1 (d), 59.4 (d), 58.7 (d), 37.1 (d), 28.8 (t),
26.2 (t), 24.2 (t), 20.9 (t) ppm.
(2S,3aS,7aS)-1-(Benzyloxycarbonyl)octahydro-1H-indole-2-carbox-
ylic Acid (8): To a solution of NaOH (2.64 g, 66 mmol, 1.1 equiv.)
in a mixture of EtOH (150 mL) and H2O (250 mL) at 10–15 °C
was added the amino acid 7 (10.2 g, 60 mmol) in one portion fol-
lowed by benzyl chloroformate (8.95 mL, 63 mmol, 1.05 equiv.)
while keeping the solution at pH = 9–10 by adding a 1  NaOH
aqueous solution. After 16 h at room temp., the EtOH was re-
moved under reduced pressure and the resulting aqueous solution
was acidified to pH = 1 by adding a 6  HCl aqueous solution.
The white residue was dissolved and extracted with CH2Cl2. The
combined organic layers were washed with brine, dried with
MgSO4, filtered, and concentrated under reduced pressure. The
crude material was purified by flash chromatography (heptane/
EtOAc gradient 30:70–0:100) to afford 8 (13.7 g, 75%) as a color-
less gum. 1H NMR (300 MHz, CDCl3, 2 rotamers): δ = 8.5 (s, 1
H), 7.40–7.26 (m, 5 H), 5.15 (d, J = 11.7 Hz, 2 H), 4.37 (m, 1 H),
3.90 (m, 1 H), 2.34 (m, 1 H), 2.20 (m, 2 H), 2.01 (m, 1 H), 1.80–1.58
(m, 3 H), 1.56–1.10 (m, 4 H) ppm. 13C NMR (50 MHz, CDCl3, 2
rotamers): δ = 178.1 (s), 177.7 (s), 155.5 (s), 154.6 (s), 137.0 (s),
136.9 (s), 128.9 (d), 128.8 (d), 128.4 (d), 128.2 (d), 127.9 (d), 67.5
(t), 59.6 (d), 59.3 (d), 58.4 (d), 58.0 (d), 37.4 (d), 36.9 (d), 33.0 (t),
31.8 (t), 28.3 (t), 27.7 (t), 26.1 (t), 24.1 (t), 20.8 (t) ppm.
(2S,3aS,7aS)-1-(tert-Butoxycarbonyl)octahydro-1H-indole-2-car-
boxylic Acid (12): To a solution of amino acid 7 (3.38 g, 20 mmol),
(Boc)2O (4.36 g, 20 mmol, 1 equiv.) and DMAP (244 mg, 2 mmol,
0.1 equiv.) in CH2Cl2 (40 mL) was added triethylamine (5.6 mL,
40 mmol, 2 equiv.). After 16 h at reflux, the mixture was cooled,
the reaction quenched by addition of a 1  HCl aqueous solution,
and the mixture extracted with CH2Cl2. The combined organic lay-
ers were washed with brine, dried with MgSO4, filtered, and con-
centrated under reduced pressure. The crude material was purified
by flash chromatography (CH2Cl2/MeOH, 95:5) to afford 12 (5.2 g,
1
97%) as a white solid. H NMR (300 MHz, CDCl3): δ = 4.29 (m,
1 H), 3.82 (m, 1 H), 2.40–1.85 (m, 4 H), 1.80–1.60 (m, 3 H), 1.60–
1.10 (m, 4 H), 1.47 (s, 9 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 173.0 (s), 154.7 (s), 79.9 (s), 59.4 (d), 57.9 (d), 37.0 (d), 28.8 (q),
28.2 (t), 28.0 (t), 26.2 (t), 24.1 (t), 20.9 (t) ppm. HRMS-EI: calcd.
224.16505 [M – COOH]+; found 224.1643.
(2S,3aS,7aS)-tert-Butyl-2-carbamoyloctahydro-1H-indole-1-carbox-
ylate (13): To a solution of amino acid 12 (269 mg, 1 mmol) in THF
(10 mL) at 0 °C under argon were successively added triethylamine
(135 µL, 0.95 mmol, 0.95 equiv.) and ethyl chloroformate (90 µL,
0.95 mmol, 0.95 equiv.). After 30 min at 0 °C, the solution was co-
oled to –78 °C, and NaNH2 (35 mg, 0.9 mmol, 0.9 equiv.) was
quickly added. The mixture was then warmed to 0 °C over 1 h,
stirred at 0 °C for 1 h, and at room temperature overnight. The
reaction was quenched by addition of H2O and the mixture ex-
tracted with CH2Cl2. The combined organic layers were washed
with brine, dried with MgSO4, filtered, and concentrated under re-
duced pressure to afford 13 (215 mg, 80%) as a white solid. 1H
NMR (200 MHz, CDCl3): δ = 4.21 (m, 1 H), 3.82 (m, 1 H), 2.35–
2.10 (m, 3 H), 1.95 (m, 1 H), 1.80–1.60 (m, 3 H), 1.58–1.15 (m, 4
(2S,3aS,7aS)-Benzyl 2-Carbamoyloctahydro-1H-indole-1-carboxyl-
ate (9): To a solution of amino acid 8 (303 mg, 1 mmol) in THF
(10 mL) at 0 °C under argon were successively added triethylamine
(135 µL, 0.95 mmol, 0.95 equiv.) and ethyl chloroformate (90 µL,
0.95 mmol, 0.95 equiv.). After 30 min at 0 °C, the solution was co-
oled to –78 °C, and NaNH2 (35 mg, 0.9 mmol, 0.9 equiv.) was
quickly added. The mixture was then warmed to 0 °C over 1 h,
stirred at 0 °C during 1 h and then at room temperature overnight.
The reaction was quenched by addition of water and the mixture
extracted with CH2Cl2. The combined organic layers were washed
with brine, dried with MgSO4, filtered, and concentrated under re-
duced pressure to afford 9 (187 mg, 62 %) as a white solid. 1H
NMR (200 MHz, CDCl3): δ = 7.40–7.20 (m, 5 H), 5.14 (m, 2 H), H), 1.47 (s, 9 H) ppm.
938
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Eur. J. Org. Chem. 2008, 934–940

New Perhydroindole Derivatives
(2S,3aS,7aS)-tert-Butyl-2-(phenylcarbamoyl)octahydro-1H-indole-1- fied by flash chromatography (heptane/ethyl acetate) to provide the
carboxylate (14): The same procedure was applied as for compound
13, replacing NaNH2 with PhNH2 to give 14 (52%). 1H NMR
(200 MHz, CDCl3): δ = 7.55 (d, J = 8.0 Hz, 2 H), 7.30 (dd, appar-
ent t, J = 7.8 Hz, 2 H), 7.07 (dd, apparent t, J = 7.3 Hz, 1 H), 4.39
(dd, apparent t, J = 8.1 Hz, 1 H), 3.91 (dt, J = 10.6, 5.4 Hz, 1 H),
2.45–2.25 (m, 2 H), 2.20–1.90 (m, 2 H), 1.80–1.60 (m, 3 H), 1.55–
1.15 (m, 5 H), 1.47 (s, 9 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 171.1 (s), 138.6 (s), 129.3 (d), 124.4 (d), 120.0 (d), 81.0 (s), 58.6
(d), 53.9 (t), 37.1 (d), 30.2 (t), 28.9 (q), 26.4 (t), 24.3 (t), 20.9 (t)
ppm.
desired alcohol.
General Hydride Transfer Procedure Using HCOOH/NEt3: [(p-cy-
mene)RuCl2]2 (6 mg, 0.01 mmol, 0.5 mol-%) and the ligand
(0.04 mmol, 2 mol-%) were stirred under argon in iPrOH (6 mL) at
reflux for 20 min. The solvent was removed under reduced pressure,
and then CH2Cl2 (0.5 mL, if noted), NEt3 (560 µL, 4 mmol,
2 equiv.), HCOOH (380 µL, 10 mmol, 5 equiv.) and the ketone
(2 mmol) were successively added, and the solution was stirred for
the indicated time under argon at room temperature (or at 45 °C if
CH2Cl2 was used). CH2Cl2 was added, the reaction was quenched
by addition of an aqueous solution of HCl (1 ), and the mixture
extracted using CH2Cl2. The combined organic layers were washed
with brine, dried with MgSO4, filtered, and concentrated under re-
duced pressure. The crude product was purified by flash
chromatography (heptane/ethyl acetate) to provide the desired
alcohol.
(2S,2ЈS,3aS,3aЈS,7aS,7aЈS)-Di-tert-butyl 2,2Ј-[Ethane-1,2-diylbis-
(azanediyl)]bis(oxomethylene)bis(octahydro-1H-indole-1-carboxyl-
ate) (15): To a solution of amino acid 12 (269 mg, 1 mmol), EDCI
(211 mg, 1.1 mmol, 1.1 equiv.), HOBt (149 mg, 1.1 mmol,
1.1 equiv.) and ethylene diamine (33 µL, 0.5 mmol, 0.5 equiv.) in
CH2Cl2 (2 mL) was added NaHCO3 (336 mg, 4 mmol, 4 equiv.).
After 24 h at room temp., the reaction was quenched by addition
of H2O and the mixture extracted with CH2Cl2. The combined ex-
tracts were successively washed with a saturated aqueous solution
of NaHCO3, a 1  HCl aqueous solution, and brine, then dried
with MgSO4, filtered, and concentrated under reduced pressure.
The crude material was purified by flash chromatography (heptane/
EtOAc) to afford 15 (473 mg, 84%) as a white solid. 1H NMR
(MHz, CDCl3): δ = 4.11 (dd, apparent t, J = 8.2 Hz, 2 H), 3.75
(m, 2 H), 3.47 (m, 2 H), 3.27 (m, 2 H), 2.34–2.10 (m, 6 H), 1.98
(m, 4 H), 1.76–1.54 (m, 6 H), 1.52–1.10 (m, 6 H), 1.43 (s, 18 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 173.7 (s), 154.5 (s), 79.8 (s),
61.1 (d), 57.8 (d), 36.8 (d), 36.8 (t), 31.4 (t), 28.5 (q), 26.0 (t), 23.9
(t), 20.5 (t) ppm. HMRS-ESI: calcd. 585.3628 [M + Na]+; found
585.3630. HMRS-EI: calcd. 562.37304[M]+; found 562.3713.
HMRS-EI: calcd. 461.31278 [M – Boc]+; found 461.3131.
In both procedures, the absolute configuration of the major enanti-
omer, and the enantiomeric excesses were determined by HPLC on
a Daicel Chiralcel OD-H chiral column.
Acknowledgments
The authors wish to thank Oril Industrie for a PhD grant to B. L.
and for a loan of (S,S,S)-perhydroindolic acid 7.
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7.22–7.09 (m, 10 H), 5.28 (br. d, J = 5.1 Hz, 2 H), 4.22 (m, 2 H),
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155.1 (s), 138.5 (s), 128.3 (d), 127.5 (d), 80.1 (s), 60.1 (d), 58.7 (d),
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Eur. J. Org. Chem. 2008, 934–940
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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B. Liégault, X. Tang, C. Bruneau, J.-L. Renaud
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Received: May 26, 2007
Published Online: December 6, 2007
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