Versatile methodology for the synthesis and α-functionalization of (2R,3aS,7aS)-octahydroindole-2-carboxylic acid

Article abstract of DOI:10.1016/j.tet.2007.10.095

An improved strategy for the effective synthesis of enantiomerically pure (2R,3aS,7aS)-octahydroindole-2-carboxylic acid (Oic), based on the?formation of a trichloromethyloxazolidinone derivative, has been developed. Additionally, the completely diastereoselective α-alkylation of such oxazolidinone provides a very convenient and concise route to enantiopure α-tetrasubstituted derivatives of this Oic stereoisomer.

Full text of DOI:10.1016/j.tet.2007.10.095

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 84e91
www.elsevier.com/locate/tet
Versatile methodology for the synthesis and a-functionalization of
(2R,3aS,7aS)-octahydroindole-2-carboxylic acid
*
´
Francisco J. Sayago, M. Isabel Calaza, Ana I. Jimenez, Carlos Cativiela
Departamento de Qu´ımica Orga´nica, Instituto de Ciencia de Materiales de Arago´n, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
Received 9 September 2007; received in revised form 19 October 2007; accepted 25 October 2007
Available online 1 November 2007
Dedicated to Miguel Yus on the occasion of his 60th birthday
Abstract
An improved strategy for the effective synthesis of enantiomerically pure (2R,3aS,7aS)-octahydroindole-2-carboxylic acid (Oic), based on
the formation of a trichloromethyloxazolidinone derivative, has been developed. Additionally, the completely diastereoselective a-alkylation
of such oxazolidinone provides a very convenient and concise route to enantiopure a-tetrasubstituted derivatives of this Oic stereoisomer.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Quaternary amino acid; Bicyclic proline analogue; Perhydroindole-2-carboxylic acid; Trichloromethyloxazolidinone; a-Alkylation; Self-reproduction
of chirality; Crystal structure
1. Introduction
very relevant for peptides and peptidomimetics because it is
related to their rate of absorption and distribution through bio-
logical membranes and, hence, to their bioactivity.4 For this
reason, the incorporation of residues of increased lipophilicity
into bioactive peptides is a convenient way to improve their
bioavailability.5
Interestingly, octahydroindole-2-carboxylic acid has been
used as a surrogate of proline and phenylalanine in bradykinin,
a linear nonapeptide hormone involved in pain and inflamma-
tion. In this way, Oic has contributed to improve the resistance
to degrading enzymes of a family of orally available bradyki-
nin B2 receptor antagonists with attractive anti-cancer proper-
ties.6 It has also been used to stabilize a type-II0 b-turn in small
cyclic peptides in order to find a starting point for the design of
alternative non-peptidic bradykinin B2 antagonists.7 In addi-
tion, Oic is a key intermediate in the preparation of medici-
nally relevant drugs like potent ACE inhibitors for the
treatment of hypertension (perindopril).8
The development of practical synthetic routes to render
enantiopure non-proteinogenic a-amino acids is receiving con-
siderable attention due to their wide applicability in engineer-
ing peptide drugs.1 The incorporation of non-coded a-amino
acids into the sequence of bioactive peptides is considered
a very useful approach to tailor their properties in order to
make therapeutic applications feasible. Such applications are
very limited due to poor metabolic stability, low bioavailabil-
ity and lack of selectivity for a specific receptor. The incorpo-
ration of non-natural a-amino acids generates modifications in
the secondary structure of these peptides and, as a result, im-
provements in selectivity and stability can often be achieved.2
Octahydroindole-2-carboxylic acid (Oic) is a non-coded
a-amino acid with a bicyclic structure that is able to introduce
certain backbone rigidity when incorporated into peptides,
similar to that induced by proline,3 and, at the same time, is
endowed with greater lipophilicity. This latter property is
Moreover, the octahydroindole-2-carboxylic acid motif
with a diverse substitution profile has been found to be part
of the structure of natural products like marine aeruginosins
with potent antithrombotic properties.9 Besides, quaternary
derivatives of Oic are the core structures of investigational
* Corresponding author. Tel./fax: þ34 976 761210.
E-mail address: cativiela@unizar.es (C. Cativiela).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.095

F.J. Sayago et al. / Tetrahedron 64 (2008) 84e91
85
H
3a
7a
H
3a
7a
enantiopure (S,S,S )-1, obtained from commercial (S )-indo-
line-2-carboxylic acid, since other retrosynthetic possibilities
from the disconnection approach do not seem to lead to
more appropriate, or easily available, starting materials.
Indeed, an improved epimerization reaction followed by
a more competitive procedure for the separation of diastereo-
isomers other than preferential crystallizations, would be
desirable for Vincent0s strategy12a to become efficient.
With this aim in mind, our synthesis began with the hydro-
genation of commercially available (S )-indoline-2-carboxylic
acid to afford diastereoisomeric (S,S,S )-1 and (S,R,R)-1 in
a 90:10 ratio (Scheme 1), in a similar way to that described
by Vincent et al.12a In our case, the use of platinum oxide as
a catalyst, instead of palladium on charcoal, allowed the hy-
drogenation to proceed at atmospheric pressure. The desired
compound (S,S,S )-1 was isolated as a pure material, in 85%
yield, after crystallization from ethanol.
2
2
COOH
COOH
N
N
H
H
H
H
(2S,3aS,7aS)-1
(S,S,S)-1
L-Oic
(2R,3aS,7aS)-1
(R,S,S)-1
Figure 1. Structure of (2S,3aS,7aS )-octahydroindole-2-carboxylic acid and its
epimer at the a carbon.
compounds with potential applications in diseases character-
ized by joint cartilage damage.10
All of the aforementioned applications involve octahy-
droindole-2-carboxylic acid with the absolute configuration
(2S,3aS,7aS ) (Fig. 1). This particular stereoisomer is usually
denoted as L-Oic, and will be referred to as (S,S,S )-1 in the fol-
lowing textda nomenclature without numerical locants is
adopted for the sake of simplicity.
The significant occurrence of this bicyclic a-amino acid has
stimulated our interest in developing efficient synthetic routes
to access the different stereoisomers of octahydroindole-2-
carboxylic acid in enantiomerically pure form. The so-called
L-Oic, (S,S,S )-1, is the only commercially available stereoiso-
mer and has therefore been the most widely used in peptidomi-
metic and medicinal chemistry research. Various strategies for
the preparation of enantiopure (S,S,S )-1 have been reported in
the literature and include stereoselective processes,11 chemical
resolutions12 of diastereoisomeric salts of (S,S,S )-1 derivatives
or their indoline precursors, and, more recently, enzymatic13
and chromatographic14 resolutions. In contrast, there is only
one reported synthesis12a of enantiomerically pure (R,S,S )-1
(Fig. 1), which involves an epimerization reaction of
(S,S,S )-1 followed by laborious crystallizations, and suffers
from a poor overall yield.
H
H
a
+
COOH
COOH
COOH
N
H
N
H
N
H
H
H
(S,S,S)-1
(S,R,R)-1
90:10
Scheme 1. Synthesis of enantiomerically pure (S,S,S )-1. Reagents and condi-
tions: (a) H2, PtO2, AcOH, 60 ꢀC. Recrystallization of the mixture from EtOH
furnishes pure (S,S,S )-1.
Enantiomerically pure (S,S,S )-1 was then submitted to
Yamada’s epimerization procedure,15 by heating in acetic
acid in the presence of a catalytic amount of salicylaldehyde
to promote the formation of a Schiff base (Scheme 2). Accord-
ing to the literature,12a the epimerization progresses to give
a 50:50 mixture of diastereoisomers after 1 h. However, we
found that a prolonged reaction time leads to a considerable
enrichment of the diastereoisomeric mixture in the desired epi-
mer, with the final ratio (S,S,S)-1/(R,S,S )-1¼23:77 after 24 h of
reaction. Undoubtedly, this represents a substantial improve-
ment and is expected to have a very positive effect on the over-
all efficiency of the method. In comparison, in the synthesis
reported by Vincent et al.,12a a 50:50 mixture of diastereoiso-
mers was obtained and used for the isolation of (R,S,S )-1. This
leads to a significant reduction in the final yield and also sets
hurdles for its isolation by recrystallization techniques.
In this paper we report a more efficient method for the con-
venient synthesis of enantiomerically pure (R,S,S )-1, which will
also allow access to a-alkyl derivatives in a concise manner.
2. Results and discussion
The preparation of enantiomerically pure (R,S,S )-1 has
only been described in the literature by Vincent et al.,12a
who used an epimerization reaction of enantiopure (S,S,S )-1
under acidic conditions, according to a general procedure re-
ported by Yamada et al.15 This approach affords a 50:50 mix-
ture of epimers from which the desired compound is isolated
after consecutive preferential crystallizations. As a result, the
synthesis becomes laborious and suffers from a low overall
isolated yield. Previously, Henning and Urbach described16
a racemic synthesis of this compound through a base-pro-
moted Favorskii-type ring contraction of an a-chlorinated lac-
tam, a process that proceeds in a quite diastereoselective
fashion. However, this approach involves more synthetic steps
and details were not given concerning the isolation of the
desired major stereoisomer (as a racemic mixture).
At this point, our efforts focused on finding a more compet-
itive way to isolate the desired compound from the 23:77
H
H
H
a
COOH
COOH
Ar
COOH
N
N
-
N
H
H
H
AcO
H
H
(S,S,S)-1
(R,S,S)-1
(S,S,S)-1 / (R,S,S)-1
100
50
23
:
:
:
0
50
77
initial
1 h
24 h
In principle, it seems that the easiest procedure for the syn-
thesis of (R,S,S )-1 would be an epimerization reaction of
Scheme 2. Epimerization of (S,S,S )-1. Reagents and conditions: (a) salicyl-
aldehyde, AcOH, reflux.

86
F.J. Sayago et al. / Tetrahedron 64 (2008) 84e91
mixture of epimers, other than laborious recrystallizations. In
doing so, we turned our attention to reported investigations
dealing with the highly stereoselective synthesis of bicyclic
oxazolidinones derived from L-proline, such as those depicted
in Scheme 3.17 This type of oxazolidinone, prepared by con-
densation of L-proline with a bulky alkyl aldehyde, has proven
to be very valuable for the synthesis of a-tetrasubstituted
prolines in enantiomerically pure form.17a,c
Cl
O
Cl
Cl
N
H
CHO
CHO
N
OH
L-proline
H
H
O
O
N
O
O
Cl
R
Cl
Cl
O
N
H
OH
α-alkyl-L-proline
Figure 2. Stick and space filling models for the theoretical trichloromethyl-
oxazolidinones derived from (R,S,S )-1 (left) and (S,S,S )-1 (right). The partially
overlapping hydrogens in (R,S,S,S )-2 are indicated.
Scheme 3. The most commonly used bicyclic oxazolidinones derived from
L-proline.
The condensation reaction gives a single diastereoisomer
with the bulky alkyl group in a cis disposition with respect
to the bridgehead hydrogen. A perspective view of the struc-
ture reveals a ‘roof’ shaped bicyclic framework, with the bulky
alkyl moiety pointing towards the less crowded convex face
(exo).17a,b
a tricyclic system with substantial steric hindrance at the inner
concave face defined by the rings. In particular, the hydrogen
at C3 is oriented towards the cyclohexane ring and would
therefore lie in close proximity to one of the hydrogens at
C6, thus producing a steric clash.
According to this observation, it seems reasonable to con-
sider that the ease of such a stereoselective condensation,
when applied to octahydroindole-2-carboxylic acids, will be
conditioned to the structural constraint of the resulting tricy-
clic system. Based on this premise, we envisaged the possibil-
ity of using this transformation as a tool for discrimination
between (R,S,S )-1 and (S,S,S )-1, where the two theoretical tri-
cyclic systems, (S,S,S,R)-2 and (R,S,S,S )-2, respectively,18
should show a priori remarkably different spatial constraints
(Fig. 2). In fact, molecular models of these structures reflect
a more sterically disfavoured situation for oxazolidinone
(R,S,S,S )-2, due to partially overlapping hydrogens at the con-
cave face defined by the tricyclic scaffold. To the best of our
knowledge, the use of this reaction for selective discrimination
between substituted epimeric prolines has not been explored,
with all previous investigations focused on the reactivity of
the oxazolidinones derived from L-proline.17,19
To test our hypothesis, the 23:77 mixture of epimers
(S,S,S )-1 and (R,S,S )-1 was treated with trichloroacetaldehyde
in acetonitrile at room temperature.20 We were delighted to
observe that, while (R,S,S )-1 reacted quantitatively with the
aldehyde, (S,S,S )-1 remained unreacted (Scheme 4). The con-
densation reaction, as in the case of L-proline, furnishes a sin-
gle compound with a new chiral centre at C3 as a result of the
trichloromethyl group being exclusively in a cis relationship
with the hydrogen in the 9a position. This experimental result
suggests that, indeed, the oxazolidinone derived from (S,S,S )-
1 (Fig. 2, right) is not formed because it would result in
H
H
COOH
COOH
+
N
H
N
H
H
H
(R,S,S)-1
(S,S,S)-1
23:77
a
H
H
O
(S,S,S)-1
+
N
H
CCl3
(S,S,S,R)-2
O
Scheme 4. Synthesis of (S,S,S,R)-2. Reagents and conditions: (a) CCl3CHO,
CH3CN, rt, 12 h.
The resulting oxazolidinone was easily isolated as a solid,
after filtration through a short pad of silica eluting with di-
chloromethane.21 Single crystals were obtained from an ethyl
acetate/hexanes solution and X-ray diffraction analysis corro-
borated the expected stereochemistry (Fig. 3). Also in this case,
the two five-membered rings define a ‘roof’ shaped structure,
with the bulky trichloromethyl group pointing towards the exo
face. The pyrrolidine ring assumes an envelope conformation
˚
with carbon 8a deviating by 0.63 A from the plane defined by
the other four atoms, which corresponds to a Cg-exo confor-
mation22 for the proline subunit. The junction to the chair of
the six-membered ring is sitting at the flap of the envelope.

F.J. Sayago et al. / Tetrahedron 64 (2008) 84e91
87
reproduction of chirality.17a The complete stereocontrol of
this process becomes particularly remarkable in comparison
with the only example of the a-alkylation of an L-Oic deriv-
ative reported to date.10 It has been shown that an N-pro-
tected methyl ester derivative of L-Oic undergoes
methylation, upon treatment with LiHMDS, to afford the
stereoisomer with retention of configuration as the major
compound, together with a non-negligible percentage of the
a-methylated epimer. In contrast, in our case, not even traces
of the other possible stereoisomer could be detected. Single
crystal X-ray diffraction analysis of the resulting a-tetrasub-
stituted compounds 3aec provided evidence for the alkyl-
ation reaction taking place with retention of configuration23
(Fig. 4).
Figure 3. X-ray crystal structure of (S,S,S,R)-2. Heteroatoms are shown as ther-
mal ellipsoids. Most hydrogens have been omitted for clarity.
The trichlomethyloxazolidinone obtained was then con-
verted to the corresponding free amino acid through hydrolysis
in acidic conditions (Scheme 5). Thus, treatment of (S,S,S,R)-2
with a saturated solution of hydrogen chloride in ethyl acetate
furnished (R,S,S )-1 in enantiomerically pure form, as the hy-
drochloride salt. It is worth noting that the overall isolated
yield of the final amino acid resulting from the epimeriza-
tionecondensationehydrolysis sequence was 56%, which rep-
resents a tremendous improvement when compared with the
30% described for direct crystallizations.12a
H
H
H
H
R
O
O
LDA, RX
N
N
O
O
THF, –78 °C
H
CCl3
(S,S,S,R)-2
CCl3
(S,S,S,R)-3a
(S,S,S,S)-3b
(S,S,S,R)-3c
yield (%)
RX
3a MeI
95
88
82
3b
3c
BnBr
AllylBr
H
H
H
H
O
Scheme 6. Synthesis of a-quaternary derivatives.
3N HCl / EtOAc
COOH
N
HCl
N
O
r.t.
93%
H
In the three crystalline structures, the pyrrolidine ring as-
sumes an envelope conformation and, as already observed
for (S,S,S,R)-2 (Fig. 3), it is the atom at the 8a position (Cg
considering the proline system) that deviates from planarity
H
CCl3
(S,S,S,R)-2
(R,S,S)-1 · HCl
Scheme 5. Isolation of the enantiomerically pure amino acid (R,S,S )-1.
˚
(0.58e0.61 A). However, in contrast to (S,S,S,R)-2, in all three
Thus, the trichlomethyloxazolidinone (S,S,S,R)-2 has
proven to be a key intermediate to allow a more efficient syn-
thesis of (R,S,S )-1. At this point, we considered that this
oxazolidinone could also be a valuable precursor to afford
a-tetrasubstituted derivatives of this Oic stereoisomer. We de-
cided to explore this possibility driven by the attractiveness of
a-alkylated Oic derivatives for peptide-engineering purposes
and the potential therapeutic value shown by structurally
related compounds for the treatment of osteoarthritis.10
Treatment of oxazolidinone (S,S,S,R)-2 with lithium diiso-
propylamide in THF at ꢁ78 ꢀC generated a lithium enolate
that successfully reacted with several alkyl electrophiles in
high yields (Scheme 6). As in the pioneering investigations
by Seebach et al.,17a we observed that both the trichloro-
methyl group and the newly introduced substituent are cis
to each other on the exo side of the bicycle constituted by
the two five-membered rings. This indicates that the enolate
underwent alkylation exclusively at the Si face. The bridge-
head nitrogen of (S,S,S,R)-2 is strongly pyramidalised and
its inversion does not take place, even when the enolate is
generated, because of the high steric constraints that such
a change would have on the system. For this reason, the eno-
late attacks the electrophile only from the face that was pre-
viously occupied by the a hydrogen, thus leading to the
formation of a single stereoisomer with retention of configu-
ration at C9a. This behaviour was named by Seebach as self-
tetrasubstituted derivatives 3aec a Cg-endo conformation22 is
observed, i.e., the flap of the envelope points in the opposite
direction. This probably helps to accommodate the newly
introduced bridgehead substituent.
These a-tetrasubstituted oxazolidinones can be hydrolyzed
in an acidic medium, although stronger conditions are re-
quired in comparison to the non-substituted analogue, as ex-
emplified for the a-methyl derivative in Scheme 7. Thus,
compound (S,S,S,R)-3a was heated under reflux in a mixture
of hydrochloric acid and acetic acid to give the free a-meth-
ylated amino acid (R,S,S )-4 as the hydrochloride salt in 92%
yield.
3. Conclusion
We have established an improved methodology for the effi-
cient synthesis of enantiomerically pure (2R,3aS,7aS )-octa-
hydroindole-2-carboxylic acid. This stereoisomer can be
efficiently separated from its epimer by means of a selective
condensation reaction with trichloroacetaldehyde. In addition,
the resulting oxazolidinone constitutes a versatile intermediate
that undergoes completely diastereoselective a-alkylation
reactions, thus providing a very convenient and concise route
to access enantiomerically pure a-alkyl derivatives of
(2R,3aS,7aS )-octahydroindole-2-carboxylic acid.

88
F.J. Sayago et al. / Tetrahedron 64 (2008) 84e91
phosphomolybdic acid (2%), CeSO4$4H2O (1%) and H2SO4
˚
(6%)]. Column chromatography was performed using 60 A
silica gel purchased from SDS. Melting points were deter-
mined on a Gallenkamp apparatus and are uncorrected. IR
spectra were registered on a Mattson Genesis or a Nicolet
Avatar 360/370 FTIR spectrophotometer; nmax is given for
1
the main absorption bands. H and 13C NMR spectra were
recorded on a Bruker AV-400 instrument at room temperature
using the residual solvent signal as the internal standard;
chemical shifts (d) are expressed in parts per million and cou-
pling constants (J ) in hertz. Optical rotations were measured
at room temperature using a JASCO P-1020 polarimeter.
High-resolution mass spectra were obtained on a Bruker
Microtof-Q spectrometer.
4.2. X-ray diffraction
Colourless single crystals of (S,S,S,R)-2 and (S,S,S,R)-3a
were obtained by slow evaporation from ethyl acetate solu-
tions. Compounds (S,S,S,S )-3b and (S,S,S,R)-3c, which are
oils, furnished single crystals upon standing. The X-ray di-
ffraction data were collected at room temperature on an Oxford
Diffraction Xcalibur diffractometer provided with a Sapphire
CCD detector, using graphite-monochromated Mo Ka radia-
˚
tion (l¼0.71073 A). The structures were solved by direct
methods using SHELXS-9724a and refinement was performed
using SHELXL-9724b by the full-matrix least-squares tech-
nique with anisotropic thermal factors for heavy atoms. Hy-
drogen atoms were located by calculation and affected by an
isotropic thermal factor fixed to 1.2 times the Ueq of the carrier
atom (1.5 for the methyl protons). Crystallographic data
(excluding structure factors) for the structures in this paper
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers CCDC
658042e658045. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: þ44(0)-1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk].
Figure 4. X-ray crystal structures of the a-tetrasubstituted oxazolidinones
(S,S,S,R)-3a, (S,S,S,S )-3b and (S,S,S,R)-3c. Heteroatoms are shown as thermal
ellipsoids. Most hydrogens have been omitted for clarity.
4. Experimental
4.1. General
4.2.1. Crystallographic data for (S,S,S,R)-2
All reagents were used as received from commercial sup-
pliers without further purification. Thin-layer chromatography
(TLC) was performed on Macherey-Nagel Polygram syl G/UV
precoated silica gel polyester plates. The products were visua-
lized by exposure to UV light (254 nm), iodine vapour or
submersion in cerium molybdate stain [aqueous solution of
˚
Orthorhombic, space group P212121; a¼8.6296(2) A,
b¼9.9887(3) A, c¼15.4787(4) A; Z¼4; dcalcd¼1.486 g cmꢁ3
;
˚
˚
7764 reflections collected, 2570 unique (Rint¼0.024); data/
parameters: 2570/155; final R indices (I>2sI ): R1¼0.028,
wR2¼0.062; final R indices (all data): R1¼0.ꢁ043 2, wR2¼
˚
0.065. Highest residual electron density: 0.18 e A
.
H
H
3a
7a
4.2.2. Crystallographic data for (S,S,S,R)-3a
Me
8a
4a
Me
COOH
HCl
O
9a
˚
6N HCl
AcOH, Δ
Orthorhombic, space group P212121; a¼8.0709(4) A,
2
N
b¼10.0848(5) A, c¼17.7838(8) A; Z¼4; dcalcd¼1.434 g cmꢁ3
;
˚
˚
N
H
3 O
H
H
92%
CCl3
(S,S,S,R)-3a
8697 reflections collected, 2868 unique (Rint¼0.026); data/
parameters: 2868/165; final R indices (I>2sI ): R1¼0.030,
wR2¼0.061; final R indices (all data): R1¼0.ꢁ043 8, wR2¼
(R,S,S)-4 · HCl
Scheme 7. Isolation of the (R,S,S ) isomer of (aMe)Oic in enantiomerically
pure form.
˚
0.065. Highest residual electron density: 0.16 e A .

F.J. Sayago et al. / Tetrahedron 64 (2008) 84e91
89
4.2.3. Crystallographic data for (S,S,S,S )-3b
66.42, 100.48, 102.14, 176.88. HRMS (ESI) C11H15Cl3NO2
[MþH]þ: calcd 298.0163, found 298.0157.
˚
Orthorhombic, space group P212121; a¼8.6469(1) A,
b¼9.5584(1) A, c¼22.3424(4) A; Z¼4; dcalcd¼1.398 g cmꢁ3
;
˚
˚
24,447 reflections collected, 4017 unique (Rint¼0.038); data/
parameters: 4017/218; final R indices (I>2sI ): R1¼0.027,
wR2¼0.050; final R indices (all data): R1¼0.ꢁ053 2, wR2¼
4.5. Synthesis of (2R,3aS,7aS )-octahydroindole-2-
carboxylic acid hydrochloride, (R,S,S )-1$HCl
˚
0.053. Highest residual electron density: 0.15 e A
.
A 3 N solution of HCl in anhydrous ethyl acetate (8 mL)
was added to (S,S,S,R)-2 (300 mg, 1.01 mmol) and the result-
ing mixture was stirred at room temperature for 24 h. The sol-
vent was concentrated in vacuo and the resulting solid was
washed with small portions of ethyl acetate to afford pure
(R,S,S )-1 as the hydrochloride salt (193 mg, 0.94 mmol, 93%
yield). Mp 176e178 ꢀC. [a]D þ29.6 (c 0.47, MeOH). IR
4.2.4. Crystallographic data for (S,S,S,R)-3c
˚
Orthorhombic, space group P212121; a¼8.7355(4) A,
b¼13.1329(5) A, c¼14.1367(5) A; Z¼4; dcalcd¼1.387 g cmꢁ3
;
˚
˚
8804 reflections collected, 2851 unique (Rint¼0.031); data/
parameters: 2851/181; final R indices (I>2sI ): R1¼0.030,
wR2¼0.058; final R indices (all data): R1¼0.ꢁ053 8, wR2¼
1
(KBr) n 3507, 3200e2300, 1732, 1578 cmꢁ1. H NMR (D2O,
400 MHz) d 1.20e1.51 (m, 5H), 1.54e1.70 (m, 2H), 1.72e
1.82 (m, 1H), 2.02e2.15 (m, 1H), 2.23e2.36 (m, 2H), 3.72
(m, 1H), 4.38 (m, 1H). 13C NMR (D2O, 100 MHz) d 20.51,
21.01, 23.95, 24.72, 32.44, 36.33, 57.61, 59.94, 172.76.
HRMS (ESI) C9H16NO2 [MꢁCl]þ: calcd 170.1176, found
170.1177.
˚
0.063. Highest residual electron density: 0.17 e A
.
4.3. Synthesis of (2S,3aS,7aS )-octahydroindole-2-
carboxylic acid, (S,S,S )-1
A
solution of (S )-indoline-2-carboxylic acid (3.0 g,
4.6. Synthesis of (3S,4aS,8aS,9aR)-9a-methyl-3-
trichloromethyloctahydrooxazolo[3,4-a]indol-1-one,
(S,S,S,R)-3a
18.38 mmol) in acetic acid (60 mL) was hydrogenated at
60 ꢀC in the presence of PtO2 (300 mg). After 24 h, the cata-
lyst was filtered off and washed with acetic acid. The solvent
was evaporated to dryness and the resulting residue was crys-
tallized from ethanol to afford pure (S,S,S )-1 as a white solid
(2.64 g, 15.60 mmol, 85% yield). Mp 267e269 ꢀC. [a]D
A 1.8 M solution of LDA in hexanes (720 mL, 1.29 mmol)
was added dropwise by syringe to a stirred solution of
(S,S,S,R)-2 (200 mg, 0.67 mmol) in anhydrous THF (3.5 mL)
at ꢁ78 ꢀC. After stirring at this temperature for 30 min,
methyl iodide (169 mL, 2.71 mmol) was added dropwise.
The resulting solution was then warmed to ꢁ50 ꢀC and stirred
at this temperature overnight. The reaction mixture was treated
with water (4 mL) and extracted with dichloromethane several
times. The combined organic layers were dried over anhydrous
MgSO4 and filtered. The solvent was concentrated in vacuo
and the residue was purified by column chromatography (elu-
ent: hexanes/ethyl acetate 10:1) to afford pure (S,S,S,R)-3a as
a white solid (200 mg, 0.64 mmol, 95% yield). Mp 134e
ꢁ45.6 (c 0.46, MeOH). IR (KBr) n 3600e2200, 1623 cmꢁ1
.
1H NMR (D2O, 400 MHz) d 1.23e1.64 (m, 7H), 1.73e1.82
(m, 1H), 1.91e2.01 (m, 1H), 2.25e2.36 (m, 2H), 3.65 (m,
1H), 4.06 (m, 1H). 13C NMR (D2O, 100 MHz) d 20.88,
21.36, 24.38, 25.06, 32.36, 36.91, 59.34, 59.70, 175.42.
HRMS (ESI) C9H16NO2 [MþH]þ: calcd 170.1176, found
170.1174.
4.4. Synthesis of (3S,4aS,8aS,9aR)-3-trichloro-
methyloctahydrooxazolo[3,4-a]indol-1-one, (S,S,S,R)-2
136 ꢀC. [a]D þ9.4 (c 0.45, CHCl3). IR (Nujol) n 1787 cmꢁ1
.
A solution of (S,S,S )-1 (2.0 g, 11.82 mmol) in acetic acid
(20 mL) was treated with salicylaldehyde (75 mL,
0.71 mmol) and heated under reflux for 24 h. The solvent
was evaporated and the residue lyophilized to furnish
a 23:77 mixture of epimers (S,S,S )-1 and (R,S,S )-1. This mix-
ture was suspended in dry acetonitrile (40 mL) and treated
with anhydrous trichloroacetaldehyde (2.0 mL, 20.50 mmol).
The resulting suspension was stirred under an argon atmo-
sphere at room temperature for 24 h. The mixture was filtered
through a pad of CeliteÒ and the filtrate was concentrated. The
residue was purified through a short pad of silica gel eluting
with dichloromethane to afford pure (S,S,S,R)-2 as a white
solid (2.11 g, 7.07 mmol, 60% yield). Mp 144e146 ꢀC (dec).
1H NMR (CDCl3, 400 MHz) d 1.09e1.22 (m, 1H), 1.23e
1.39 (m, 2H), 1.47e1.66 (m, 2H) overlapped with 1.62 (s, 3H),
1.68e1.85 (m, 2H), 1.88e1.97 (m, 1H), 2.02 (m, 1H),
2.15e2.30 (m, 2H), 3.15 (m, 1H), 5.05 (s, 1H). 13C NMR
(CDCl3, 100 MHz) d 19.95, 24.50, 24.96, 27.43, 28.79,
36.98, 40.88, 68.77, 70.45, 100.41, 102.35, 177.84. HRMS
(ESI) C12H17Cl3NO2 [MþH]þ: calcd 312.0319, found
312.0320.
4.7. Synthesis of (3S,4aS,8aS,9aS )-9a-benzyl-3-
trichloromethyloctahydrooxazolo[3,4-a]indol-1-one,
(S,S,S,S )-3b
[a]D þ59.4 (c 0.47, CHCl3). IR (Nujol) n 1739 cmꢁ1
.
1H
Using benzyl bromide (326 mL, 2.74 mmol) as the alkyl-
ating agent, an identical procedure to that described above
was applied to the transformation of (S,S,S,R)-2 (200 mg,
0.67 mmol) into (S,S,S,S )-3b (230 mg, 0.59 mmol, 88%
yield). The product was isolated as an oil that crystallized
NMR (CDCl3, 400 MHz) d 1.20e1.48 (m, 3H), 1.54e1.71 (m,
4H), 1.87 (m, 1H), 1.96e2.20 (m, 3H), 3.18 (m, 1H), 4.27 (dd,
1H, J¼8.8, 7.2 Hz), 5.18 (s, 1H). 13C NMR (CDCl3,
100 MHz) d 20.26, 23.62, 26.80, 27.67, 34.46, 38.49, 61.27,

90
F.J. Sayago et al. / Tetrahedron 64 (2008) 84e91
upon standing. Mp 150e151 ꢀC. [a]D ꢁ26.6 (c 0.48, CHCl3).
IR (Nujol) n 1794 cmꢁ1. 1H NMR (CDCl3, 400 MHz) d 0.80e
0.97 (m, 2H), 1.23e1.59 (m, 5H), 1.71 (m, 1H), 1.97e2.22
(m, 3H), 2.91e3.09 (m, 2H), 3.29 (d, 1H, J¼13.8 Hz), 5.12
(s, 1H), 7.21e7.36 (m, 5H). 13C NMR (CDCl3, 100 MHz)
d 19.91, 24.43, 25.00, 27.67, 35.84, 36.26, 42.32, 71.45,
72.58, 100.04, 103.48, 127.13, 127.93, 131.63, 135.28,
177.42. HRMS (ESI) C18H20Cl3NNaO2 [MþNa]þ: calcd
410.0452, found 410.0443.
N01-CO-12400. The content of this publication does not nec-
essarily reflect the view of the policies of the Department of
Health and Human Services, nor does mention of trade names,
commercial products, or organization imply endorsement by
the U.S. Government. This research was supported (in part)
by the Intramural Research Program of the NIH, National
Cancer Institute, Center for Cancer Research.
References and notes
4.8. Synthesis of (3S,4aS,8aS,9aR)-9a-allyl-3-
trichloromethyloctahydrooxazolo[3,4-a]indol-1-one,
(S,S,S,R)-3c
1. Adessi, C.; Soto, C. Curr. Med. Chem. 2002, 9, 963e978.
2. (a) Cowell, S. M.; Lee, Y. S.; Cain, J. P.; Hruby, V. J. Curr. Med. Chem.
2004, 11, 2785e2798; (b) Toniolo, C.; Crisma, M.; Formaggio, F.;
Peggion, C. Biopolymers (Pept. Sci.) 2001, 60, 396e419; (c) Hruby,
V. J.; Li, G.; Haskell-Luevano, C.; Shenderovich, M. Biopolymers (Pept.
Sci.) 1997, 43, 219e266.
Using allyl bromide (237 mL, 2.74 mmol) as the alkylating
agent, an analogous procedure to that described above, al-
lowed the transformation of (S,S,S,R)-2 (200 mg, 0.67 mmol)
into (S,S,S,R)-3c (185 mg, 0.55 mmol, 82% yield), which
was isolated as an oil that crystallized upon standing. Mp
114e115 ꢀC. [a]D ꢁ3.3 (c 0.48, CHCl3). IR (Nujol)
3. Karoyan, P.; Sagan, S.; Lequin, O.; Quancard, J.; Lavielle, S.; Chassaing,
G. Substituted Prolines: Syntheses and Applications in StructureeActivity
Relationship Studies of Biologically Active Peptides. Targets in Hetero-
cyclic Systems: Chemistry and Properties; Attanasi, O. A., Spinelli, D.,
Eds.; Royal Society of Chemistry: Cambridge, 2005; Vol. 8, pp 216e273.
4. van de Waterbeemd, H.; Karajiannis, H.; El Tayar, N. Amino Acids 1994,
7, 129e145.
1
n 1791 cmꢁ1. H NMR (CDCl3, 400 MHz) d 1.04e1.18 (m,
1H), 1.19e1.39 (m, 2H), 1.43e1.64 (m, 2H), 1.65e1.75 (m,
1H), 1.76e1.90 (m, 2H), 1.98e2.23 (m, 3H), 2.54 (ddd, 1H,
J¼14.0, 7.1, 0.9 Hz), 2.72 (dd, 1H, J¼14.0, 7.6 Hz), 3.12
(m, 1H), 5.08 (s, 1H), 5.11e5.23 (m, 2H), 5.97 (m, 1H). 13C
NMR (CDCl3, 100 MHz) d 20.09, 24.57, 25.07, 28.57,
36.46, 36.79, 43.56, 70.75, 71.17, 100.08, 102.88, 119.24,
132.67, 176.86. HRMS (ESI) C14H19Cl3NO2 [MþH]þ: calcd
338.0476, found 338.0463.
5. El Tayar, N.; Karajiannis, H.; van de Waterbeemd, H. Amino Acids 1995,
8, 125e139.
6. (a) Reissmann, S.; Imhof, D. Curr. Med. Chem. 2004, 11, 2823e2844; (b)
Stewart, J. M. Peptides 2004, 25, 527e532.
7. Monteagudo, E. S.; Calvani, F.; Catrambone, F.; Fincham, C. I.; Madami,
A.; Meini, S.; Terracciano, R. J. Pept. Sci. 2001, 7, 270e283.
8. (a) Alfakih, K.; Hall, A. S. Expert Opin. Pharmacother. 2006, 7, 63e71;
(b) Hurst, M.; Jarvis, B. Drugs 2001, 61, 867e896; (c) Todd, P. A.; Fitton,
A. Drugs 1991, 42, 90e114.
9. (a) Hanessian, S.; Del Valle, J. R.; Xue, Y.; Blomberg, N. J. Am. Chem.
Soc. 2006, 128, 10491e10495; (b) Hanessian, S.; Tremblay, M.; Petersen,
J. F. W. J. Am. Chem. Soc. 2004, 126, 6064e6071; (c) Carroll, A. R.;
Pierens, G. K.; Fechner, G.; de Almeida Leone, P.; Ngo, A.; Simpson,
4.9. Synthesis of (2R,3aS,7aS )-2-methyl-
octahydroindole-2-carboxylic acid hydrochloride,
(R,S,S )-4$HCl
M.; Hyde, E.; Hooper, J. N. A.; Bostrom, S.-L.; Musil, D.; Quinn, R. J.
¨
J. Am. Chem. Soc. 2002, 124, 13340e13341.
10. Barvian, N. C.; Connolly, C. J. C.; Guzzo, P. R.; Hamby, J. M.; Hicks, J.
L.; Johnson, M. R.; Le, V.-D.; Mitchell, L. H.; Roark, W. H. PCT Patent
WO 2004092132, 2004.
Acetic acid (4 mL) and 6 N HCl (4 mL) were added to
(S,S,S,R)-3a (200 mg, 0.64 mmol) and the reaction mixture
was heated under reflux for 12 h. The solvent was concen-
trated in vacuo and the resulting solid was washed with small
portions of ethyl acetate to afford pure (R,S,S )-4 as the hydro-
chloride salt (130 mg, 0.59 mmol, 92% yield). Mp 206e
208 ꢀC. [a]D þ28.2 (c 0.47, MeOH). IR (KBr) n 3434,
11. (a) Belvisi, L.; Colombo, L.; Colombo, M.; Di Giacomo, M.; Manzoni, L.;
Vodopivec, B.; Scolastico, C. Tetrahedron 2001, 57, 6463e6473; (b)
Pyne, S. G.; Javidan, A.; Skelton, B. W.; White, A. H. Tetrahedron
1995, 51, 5157e5168.
12. (a) Vincent, M.; Marchand, B.; Remond, G.; Jaguelin-Guinamant, S.;
Damien, G.; Portevin, B.; Baumal, J.-Y.; Volland, J.-P.; Bouchet, J.-P.;
Lambert, P.-H.; Serkiz, B.; Luitjen, W.; Laubie, M.; Schiavi, P. Drug
Des. Discov. 1992, 9, 11e28; (b) Blankley, C. J.; Kaltenbronn, J. S.;
DeJohn, D. E.; Werner, A.; Bennett, L. R.; Bobowski, G.; Krolls, U.;
Johnson, D. R.; Pearlman, W. M.; Hoefle, M. L.; Essenburg, A. D.; Cohen,
D. M.; Kaplan, H. R. J. Med. Chem. 1987, 30, 992e998; (c) Vincent, M.;
Remond, G.; Portevin, B.; Serkiz, B.; Laubie, M. Tetrahedron Lett. 1982,
23, 1677e1680.
3200e2200, 1731, 1591 cmꢁ1 1H NMR (D2O, 400 MHz)
.
d 1.18e1.71 (m, 7H) overlapped with 1.65 (s, 3H), 1.78e1.89
(m, 1H), 2.07 (dd, 1H, J¼17.1, 12.9 Hz), 2.29 (m, 1H), 2.39
(dd, 1H, J¼17.1, 8.9 Hz), 3.74 (m, 1H). 13C NMR (D2O,
100 MHz) d 20.19, 21.73, 23.37, 24.85, 24.93, 36.09, 39.02,
59.85, 68.59, 175.45. HRMS (ESI) C10H18NO2 [MꢁCl]þ:
calcd 184.1332, found 184.1341.
13. Hirata, N. U.S. Patent 0,106,690, 2005.
´
14. Sayago, F. J.; Jimenez, A. I.; Cativiela, C. Tetrahedron: Asymmetry 2007,
18, 2358e2364.
Acknowledgements
15. Yamada, S.; Hongo, C.; Yoshioka, R.; Chibata, I. J. Org. Chem. 1983, 48,
843e846.
´
Financial support from the Ministerio de Educacion y Cien-
ciaeFEDER (project CTQ2004-5358) and Gobierno de
16. Henning, R.; Urbach, H. Tetrahedron Lett. 1983, 24, 5339e5342.
17. (a) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem. Soc.
1983, 105, 5390e5398; (b) Orsini, F.; Pelizzoni, F.; Forte, M.; Sisti, M.;
Bombieri, G.; Benetollo, F. J. Heterocycl. Chem. 1989, 26, 837e841; (c)
Germanas, J. P.; Wang, H. Synlett 1999, 33e36.
´
Aragon (project PIP206/2005 and research group E40) is
gratefully acknowledged. This project has been funded in
whole or in part with Federal funds from the National Cancer
Institute, National Institutes of Health, under contract number
18. Note that the order of stereochemical descriptors R/S obey different numer-
ation profiles in compounds 1 and 2. In particular, the a carbon occupies

F.J. Sayago et al. / Tetrahedron 64 (2008) 84e91
91
position 2 in the former and position 9a in the latter. Abbreviated names,
with and without numerical locants, are exemplified below for clarity.
while the tert-butyl derivative is highly sensitive to hydrolysis and unsta-
ble in air.
21. Unreacted (S,S,S)-1 can be isolated, if desired, by washing the silica pad
with MeOH.
H
3a
7a
H
8a
4a
8
5
4
7
9
3
H
7
6
5
6
22. (a) DeTar, D. F.; Luthra, N. P. J. Am. Chem. Soc. 1977, 99, 1232e1244;
(b) Ashida, T.; Kakudo, M. Bull. Chem. Soc. Jpn. 1974, 47, 1129e
1133.
2
O
9a
1
COOH
1
N
N
2
4
O
H
H
H
3
23. Although the relative spatial disposition of substituents at carbon 9a
is identical for all three tetrasubstituted compounds 3aec, the stereochem-
ical descriptors R/S giving the absolute configuration of the carbon centre
differ. Thus, the compound with a benzyl substituent (3b) has an S config-
uration at position 9a due to the different priority of the substituents in
comparison with the methyl or allyl derivatives.
CCl3
(2R,3aS,7aS)-1
(R,S,S)-1
(3S,4aS,8aS,9aR)-2
(S,S,S,R)-2
19. Amedjkouh, M.; Ahlberg, P. Tetrahedron: Asymmetry 2002, 13, 2229e
2234.
24. (a) Sheldrick, G. M. SHELXS-97, Program for the Solution of Crystal
Structures; University of Gottingen: Gottingen, 1997; (b) Sheldrick,
¨ ¨
20. The preparation of trichloromethyloxazolidinones was preferred to tert-
butyloxazolidinones because of their greater stability. In the case of pro-
line, the corresponding trichloromethyloxazolidinone is a crystalline solid,
G. M. SHELXL-97, Program for the Refinement of Crystal Structures;
University of Gottingen: Gottingen, 1997.
¨
¨