A straightforward route to enantiopure α-substituted derivatives of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid

Article abstract of DOI:10.1016/j.tet.2009.05.006

High yielding and remarkably selective alkylations of a suitably protected derivative of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid are described. The fused bicyclic structure of this proline analogue greatly influences the stereochemical outcome of d

Full text of DOI:10.1016/j.tet.2009.05.006

Tetrahedron 65 (2009) 5174–5180
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Tetrahedron
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A straightforward route to enantiopure
a-substituted derivatives
of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid
*
´
Francisco J. Sayago, M. Isabel Calaza, Ana I. Jimenez, Carlos Cativiela
´
´
Departamento de Qu´ımica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza–CSIC, 50009 Zaragoza, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 April 2009
Received in revised form 2 May 2009
Accepted 5 May 2009
Available online 9 May 2009
High yielding and remarkably selective alkylations of a suitably protected derivative of (2S,3aS,7aS)-
octahydroindole-2-carboxylic acid are described. The fused bicyclic structure of this proline analogue
greatly influences the stereochemical outcome of direct alkylation reactions taking place at the
and provides access to -substituted analogues with retention of the configuration. The overall pro-
cedure allows the preparation of enantiopure -substituted derivatives of this Oic isomer, suitably
protected for their incorporation into peptides, in a straightforward manner.
Ó 2009 Elsevier Ltd. All rights reserved.
a-carbon
a
a
Dedicated to Professor Josep Font on the
occasion of his 70th birthday
Keywords:
Quaternary amino acid
Bicyclic proline analogue
Perhydroindole-2-carboxylic acid
a
-Alkylation
1. Introduction
Moreover, Oic has been useful to improve the affinity towards
certain receptors by providing better hydrophobic recognition in-
teractions at the binding-site.3 Additionally, some applications of
Oic derivatives have been reported in the field of catalysis.4
However, the exploitation of this fused bicyclic proline analogue
is far from complete because its stereochemical diversity and
functionalization remains barely explored. Nearly all of the afore-
mentioned applications refer to (2S,3aS,7aS)-Oic5 (Fig. 1) and, in-
deed, most of the reported procedures describe the preparation of
this particular Oic stereoisomer.6
Octahydroindole-2-carboxylic acid (Oic, Fig. 1) is a proline an-
alogue that is considered to be a very useful scaffold for the opti-
mization of pharmacologically active peptides.1 Particularly notable
has been the use of Oic in the design of angiotensin-converting
enzyme (ACE) inhibitors,1a,b,f antagonists for the B2 receptor of
bradykinin hormone1c–e and prolyl oligopeptidase (POP) inhib-
itors.1g,h Due to its bicyclic structure and lipophilicity, the in-
corporation of Oic into peptides may be of help to overcome
important limitations to the usefulness of small peptides as drugs,
such as their great conformational flexibility in solution, their low
stability towards proteolytic enzymes and poor bioavailability.2
In the context of functionalized Oic derivatives, synthetic effort
has been primarily oriented to the preparation of 6-substituted 2-
carboxy octahydroindoles7b–e because they constitute the core
subunit of a family of marine metabolites (aeruginosins) with
activity as protease inhibitors. Besides this substitution pattern,
H
a
-substituted Oic derivatives7a are very attractive scaffolds as they
are the core structure of compounds with anti-arthritic activity. Even
more importantly, as
-substituted proline analogues,8 they are of
3a
2
*
COOH
COOH
*
*
N
N
H
7a
a
H
H
high intrinsic value in the design of modified peptides. Due to their
conformationally well-defined structures,9 their incorporation into
peptides would cause constraints that may lead to enhanced af-
finity, resistance to proteolysis and bioavailability. Additionally,
they could serve as tools to elucidate the bioactive conformations of
peptides or the three-dimensional structures of protein receptors.
Oic
(2S,3aS,7aS)-Oic
(S,S,S)-Oic
Figure 1. Structure of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid.
However, despite their potential value, the preparation of
a-
* Corresponding author. Tel./fax: þ34 976 761 210.
E-mail address: cativiela@unizar.es (C. Cativiela).
tetrasubstituted Oic analogues remains almost unexplored.7a,10
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.006

F.J. Sayago et al. / Tetrahedron 65 (2009) 5174–5180
5175
This observation has stimulated our interest in developing efficient
routes to produce the different stereoisomers of -substituted
octahydroindole-2-carboxylic acids in enantiomerically pure
formdin particular, those with a cis-fused bicyclic structure.
In this context, we have recently described a versatile meth-
would easily allow the preparation of
a
-substituted derivatives
a
suitably protected for their incorporation into peptides. Thus,
(S,S,S)-4 was prepared from enantiomerically pure (S,S,S)-1, which
in turn was synthesized by hydrogenation of commercially avail-
able (S)-indoline-2-carboxylic acid as described previously.6g Pro-
tection of the carboxylic acid and amino functionalities in (S,S,S)-1
was carried out by treatment with methanol in the presence of
thionyl chloride and subsequent reaction with di-tert-butyl dicar-
bonate (Scheme 2).
odology that provides access to enantiopure
rivatives of (R,S,S)-Oic that have a cis disposition of the hydrogen
atoms at the ring junction and the
-carboxyl group (Scheme 1).10a
a-substituted de-
a
The procedure involves a stereocontrolled carbon–carbon bond-
forming reaction on the trichloromethyloxazolidinone (S,S,S,R)-2
derived from (R,S,S)-Oic [(R,S,S)-1] as the precursor amino acid.10a
This methodology is based on Seebach’s self-reproduction of chi-
rality principle.11 The proccess involves the generation of an
endocyclic lithium enolate, which undergoes alkylation exclusively
H
H
a
COOH
COOMe
93%
N
H
N
H
H
H
at the face previously occupied by the
a hydrogen. The cyclic nature
(S,S,S)-1
(S,S,S)-3
of the enolate prevents the inversion of the pyramidalized
bridgehead nitrogen and ensures absolute stereocontrol towards
products with retention of configuration.
b
96%
H
H
H
H
H
COOMe
N
Boc
COOH
COOH
N
H
N
H
(S,S,S)-4
H
(R,S,S)-Oic
(R,S,S)-1
(S,S,S)-Oic
Scheme 2. Synthesis of enantiopure (S,S,S)-4. Reagents and conditions: (a) SOCl2,
MeOH, rt; (b) Boc2O, i-Pr2EtN, 4-dimethylaminopyridine, THF, rt.
(S,S,S)-1
X
Cl3CCHO
The treatment of (S,S,S)-4 with LDA in THF at ꢀ78 ꢁC generated
an intermediate lithium enolate that successfully reacted with
methyl iodide to afford (S,S,S)/(R,S,S)-5a in high yield (Scheme 3).
Despite this initial good result, the effectiveness of other bases was
evaluated. In comparison, the use of either LHMDS or KHMDS as
a base led to poor conversions (w50%) under similar reaction
conditions. Thus, LDA was also the base of choice for the synthesis
H
H
H
H
8a
O
O
9a
N
4a
N
H
3
O
O
H
CCl3
CCl3
(3S,4aS,8aS,9aR)-2
(3R,4aS,8aS,9aS)-2
(S,S,S,R)-2
(R,S,S,S)-2
of
a-allyl and a-benzyl derivatives. The diastereomeric mixtures
1) RX
2) H+
(S,S,S)/(R,S,S)-5b and (S,S,S)/(R,S,S)-5c were isolated, after 12 h of
reaction at ꢀ50 ꢁC with allyl bromide and benzyl bromide, in 83
and 97% yields, respectively.
H
H
COOH
R
R
COOH
N
H
N
H
H
H
(αR)-(R,S,S)-Oic
(αR)-(S,S,S)-Oic
H
Scheme 1. Reported synthesis for
a
-alkyl derivatives of (R,S,S)-Oic (Ref. 10a).
COOMe
N
Boc
H
Unfortunately, this powerful procedure cannot be applied to the
preparation of epimeric -substituted (S,S,S)-Oic derivatives be-
(S,S,S)-4
a
a
cause the precursor amino acid fails to undergo condensation with
trichloroacetaldehyde to produce the corresponding oxazolidinone
[(R,S,S,S)-2, (Scheme 1)].10a The steric hindrance introduced by the
cyclohexane group in (S,S,S)-1, which has a cis orientation relative
to the carboxylic function, prevents the formation of the
oxazolidinone.
In contrast, the same spatial perturbation should have a bene-
ficial effect on the facial selectivity of direct alkylations taking place
on an exocyclic enolate derived from a suitable derivative of (S,S,S)-
1. In the present work we wish to report the convenience of such an
alternative method for the straightforward preparation of enan-
H
H
H
H
H
H
c
b
R
R
R
COOMe
COOMe
Boc
COOMe
H
HCl
N
Boc
N
N
(S,S,S)/(R,S,S)-5a 92%
(S,S,S)-5a 75%
(S,S,S)-6a 95%
83%
97%
71%
77%
98%
96%
(S,S,S)/(R,S,S)-5b
(S,S,S)/(R,S,S)-5c
(S,S,S)-5b
(R,S,S)-5c
(S,S,S)-6b
(R,S,S)-6c
quant.
b
H
H
R
tiopure a-substituted Oic analogues with a cis relative disposition
COOMe
HCl
of the hydrogen atoms at the ring junction and the newly in-
troduced substituent. Preliminary results of this work have been
communicated in part.10b
N
H
dr
(S,S,S)/(R,S,S)-6a
(S,S,S)/(R,S,S)-6b
(S,S,S)/(R,S,S)-6c
89:11
90:10
86:14
a: R = Me b: R = Allyl
c: R = Bn
2. Results and discussion
Scheme 3.
a
-Alkylations of (S,S,S)-4. Reagents and conditions: (a) LDA, RX, THF, ꢀ78 to
ꢀ50 ꢁC; (b) 3 N HCl/EtOAc, rt; (c) column chromatography of the diastereomeric
mixtures (SiO2, EtOAc/hexanes 1:10) furnishes pure (S,S,S)-5a, (S,S,S)-5b and (R,S,S)-5c.
RX¼MeI, AllylBr, BnBr.
The N-Boc amino ester (S,S,S)-4 (Scheme 2) was selected as the
precursor to evaluate the functionalization at the
a carbon, since it

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F.J. Sayago et al. / Tetrahedron 65 (2009) 5174–5180
The diastereomeric ratios (drw90:10) were established by
analysis of the relative intensities of appropriate signals in the 1H
NMR spectra of the mixture of the amino ester hydrochlorides
(S,S,S)/(R,S,S)-6a–c,12 which were quantitatively obtained by treat-
ment of the crude mixtures of (S,S,S)/(R,S,S)-5a–c with a saturated
solution of hydrogen chloride in ethyl acetate (Scheme 3).
In each case, the absolute configuration of the major isomer was
established by comparison of the 1H NMR spectra of the crude
mixture of the amino ester hydrochlorides (S,S,S)/(R,S,S)-6a–c with
samples of enantiopure (R,S,S)-6a, (R,S,S)-6b and (S,S,S)-6c
(Scheme 4).13 The latter
a
-substituted Oic derivatives are charac-
terized by a cis relative disposition of the hydrogen atoms at the
ring junction and the -carboxyl group, and were prepared from
a
the corresponding enantiopure oxazolidinones 7a–c. Thus, oxazo-
lidinones 7a–c, obtained from (S,S,S,R)-2 (Scheme 1) as reported
previously,10a were treated with sodium methoxide in methanol to
afford N-formylated amino ester intermediates. These compounds
were progressed to the desired amino ester hydrochlorides by
heating under reflux in the presence of acetyl chloride (Scheme 4).
Figure 2. X-ray crystal structures of (S,S,S)-6a (the chlorine atom is not shown) and
(R,S,S)-5c. Heteroatoms are drawn as thermal ellipsoids. Most hydrogens have been
omitted for clarity.
H
H
R
O
a, b
COOMe
R
N
nature of the alkylating reagent due to stereoelectronic factors.15
Thus, contrary to expectations based on 1,3-steric hindrance, ali-
phatic halides preferentially react from the face cis to the sub-
N
O
H
H
H HCl
CCl3
(S,S,S,R)-7a
(S,S,S,R)-7b
(S,S,S,S)-7c
(R,S,S)-6a
80%
(R,S,S)-6b 78%
75%
R = Me
R = Allyl
R = Bn
stituent in the ring. In comparison, halides containing
react from the less hindered face. On the other hand, enolates de-
rived from N-Boc- -proline methyl esters substituted either at C3 or
p-systems
(S,S,S)-6c
L
Scheme 4. Synthesis of enantiopure (R,S,S)-6a, (R,S,S)-6b and (S,S,S)-6c. Reagents and
C5 have been reported to react with the incoming electrophiles
from the face trans to the substituent in the ring.16 However,
meaningful comparisons are not straightforward as it has been
shown that the stereocontrol is strongly dependent on the nature of
the N-protecting group.15,17
In our case, the steric hindrance imposed by the cis-fused cy-
clohexane ring allows an efficient facial stereodifferentiation on the
exocyclic enolate that translates into a good diastereoselectivity
during the alkylation reaction. Presumably, the concave face of the
bicyclic system reflects a more sterically disfavouring situation due
to the hydrogens of the cyclohexyl ring, at positions 4 and 6, lying
towards the trajectory of the incoming electrophile.
conditions: (a) MeONa, MeOH, rt; (b) CH3COCl, MeOH, reflux.
The methyl amino esters (R,S,S)-6a, (R,S,S)-6b and (S,S,S)-6c thus
obtained showed spectroscopic data identical to those of the minor
stereoisomer in the crude mixtures of (S,S,S)/(R,S,S)-6a–c. There-
fore, the enolate generated from (S,S,S)-4 undergoes alkylation at
the Re face to preferentially furnish the isomer with retention of
configuration at the
a carbon.
In all cases, the major diastereoisomer of the crude mixture,
(S,S,S)-6a, (S,S,S)-6b or (R,S,S)-6c could be isolated pure and in good
yield (71–77%) after column chromatography (Scheme 3). Sub-
sequent treatment of these compounds in acidic conditions led to
the corresponding amino ester hydrochlorides in nearly quantita-
tive yields.
In order to evaluate whether the stereocontrol during the car-
bon–carbon bond forming reaction is purely driven by this steric
effect, the
a-methylation reaction was undertaken on epimeric
At this stage, the amino ester hydrochloride (S,S,S)-6a and the N-
Boc protected derivative (R,S,S)-5c furnished single crystals suitable
for X-ray diffraction analysis. The crystal structures (Fig. 2) cor-
roborated the previously assigned stereochemistry, with both
compounds exhibiting a cis relative disposition of the hydrogen
atoms at the ring junction and the newly introduced substituent.
The boat conformation adopted by the cyclohexane ring in the
crystal structure of (S,S,S)-6a is noteworthy. In this compound,
the pyrrolidine ring assumes a Ca-envelope conformation in which
(R,S,S)-4. This compound was prepared from enantiopure (R,S,S)-
110a as previously described for (S,S,S)-4 (Scheme 2). Thus, treat-
ment of (R,S,S)-4 with LDA in THF at ꢀ78 ꢁC generated a lithium
enolate that reacted with methyl iodide to furnish an 89:11 di-
astereoisomeric mixture identical to that obtained before from
(S,S,S)-4, with (S,S,S)-6a being the major isomer (Scheme 5).
According to this observation, both epimers are suitable precursors
for the preparation of a-tetrasubstituted derivatives of (S,S,S)-Oic
since they give rise to the same intermediate enolate.
the bulkiest substituent at the
a carbon is located in a pseudo-
equatorial position. In comparison, the six-membered ring in
(R,S,S)-5c adopts a chair disposition and the pyrrolidine moiety
exhibits an envelope conformation, with carbon atom 3a occupying
the flap of the envelope. This corresponds to a Cg-exo conforma-
tion14 for the proline subunit.
H
H
a, b
Me
COOMe
COOMe
N
H
N
H
H
Boc
(R,S,S)-4
HCl
The stereoselectivity attained during the a-alkylation reactions
(S,S,S)/(R,S,S)-6a
89:11
on (S,S,S)-4 is rather significant given the complex stereochemical
problems that can arise in the alkylation of enolates derived from
proline esters with additional substituents at the pyrrolidine ring.
In fact, the diastereofacial differentiation of the lithium enolate
Scheme 5.
a-Methylation reaction of (R,S,S)-4. Reagents and conditions: (a) LDA, MeI,
THF, ꢀ78 to ꢀ50 ꢁC; (b) 3 N HCl/EtOAc, rt.
generated from trans-4-silyloxy-N-Boc-L-proline methyl esters, by
Additionally, the preparation of a-alkyl derivatives of (S,S,S)-Oic
treatment with LDA, has been reported to be dependent on the
suitably protected for their incorporation into peptides was

F.J. Sayago et al. / Tetrahedron 65 (2009) 5174–5180
5177
exemplified with the synthesis of compound (S,S,S)-8, which bears
a free carboxylic group and a Boc-protected amino function
Oxford Diffraction Xcalibur diffractometer provided with a Sap-
phire CCD detector, using graphite-monochromated Mo K radia-
tion (
¼0.71073 Å). The structures were solved by direct methods
a
(Scheme 6). Thus, the
a-methyl derivative (S,S,S)-5a was heated
l
under reflux in a methanolic solution of potassium hydroxide to
afford the desired N-Boc amino acid (S,S,S)-8 in excellent yield.
using SHELXS-9718a and refinement was performed using SHELXL-
9718b by the full-matrix least-squares technique with anisotropic
thermal factors for heavy atoms. Hydrogen atoms were located by
calculation (with the exception of the amine protons, which were
found on the E-map) 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 num-
bers CCDC 725593 and 694571. 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].
Crystallographic data for (R,S,S)-5c: trigonal, space group P32; a,
b¼9.9849(3) Å, c¼18.0716(7) Å; Z¼3; dcalcd¼1.192 g cmꢀ3; 30,858
reflections collected, 4207 unique (Rint¼0.039); data/parameters:
H
H
H
H
a
Me
Me
COOMe
COOH
92%
N
N
Boc
Boc
(S,S,S)-5a
(S,S,S)-8a
Scheme 6. Synthesis of enantiopure (S,S,S)-8a. Reagents and conditions: (a) 1 N KOH,
MeOH/H2O, reflux.
3. Conclusion
a
-Substituted derivatives of (S,S,S)-Oic with a cis relative dis-
position of the hydrogen atoms at the ring junction and the newly
introduced substituent can be accessed by means of highly dia-
stereoselective a-alkylation reactions on (S,S,S)-4. The facial ster-
4207/246; final R indices (I>2
indices (all data): R1¼0.051, wR2¼0.067. Highest residual electron
density: 0.09 e Åꢀ3
s
I): R1¼0.030, wR2¼0.063; final R
.
eodifferentiation imposed by the cyclohexane ring on the exocyclic
enolate derived from (S,S,S)-4 accounts for the selective outcome of
the alkylation reactions. Alternatively, identical results can be
achieved by using the epimeric compound, (R,S,S)-4, as the starting
amino ester. Remarkable percentages of retention of configuration
Crystallographic data for (S,S,S)-6a: orthorhombic, space group
P212121; a¼7.7814(2) Å, b¼8.9278(4) Å, c¼17.6054(7) Å; Z¼4;
dcalcd¼1.269 g cmꢀ3
; 8032 reflections collected, 2640 unique
(Rint¼0.021); data/parameters: 2640/137; final R indices (I>2
sI):
R1¼0.025, wR2¼0.060; final
R
indices (all data): R1¼0.031,
wR2¼0.061. Highest residual electron density: 0.23 e Åꢀ3
.
at the
a carbon can be attained regardless of the open nature of the
enolate intermediate or the steric and electronic characteristics of
the electrophiles. Such a spatial effect can thus be regarded as a tool
for stereocontrol induction during the functionalization at the
4.3. Synthesis of methyl (2S,3aS,7aS)-octahydroindole-
2-carboxylate, (S,S,S)-3
a
carbon for those sterically hindered proline-type substrates
where the generation of an endocyclic enolate, through the prep-
Thionyl chloride (2.8 mL, 38.12 mmol) was added dropwise to an
ice-cooled solution of (2S,3aS,7aS)-octahydroindole-2-carboxylic
acid6g (3.11 g, 18.39 mmol) in dry methanol (47 mL). The resulting
solution was stirred at room temperature for 24 h. The solvent was
concentrated in vacuo and the resulting residue was lyophilized
and washed with small portions of ethyl acetate to afford pure
(S,S,S)-3 as a white solid (3.76 g, 17.10 mmol, 93% yield). Mp 169–
aration of
possible.
a trichloromethyloxazolidinone precursor, is not
4. Experimental
4.1. General
171 ꢁC. [
730 cmꢀ1. 1H NMR (MeOD, 400 MHz)
1H), 2.18 (dt, 1H, J¼12.6, 9.3 Hz), 2.41–2.54 (m, 2H), 3.76 (m, 1H),
3.88 (s, 3H), 4.51 (m, 1H). 13C NMR (MeOD, 100 MHz)
21.31, 23.65,
25.59, 25.95, 32.07, 38.44, 54.15, 59.34, 60.89, 171.51. HRMS (ESI)
C10H18NO2 Mþ: calcd 184.1332, found 184.1339.
a
]
D
ꢀ19.4 (c 0.50, MeOH). IR (Nujol)
n
1743, 1460, 1226,
All reagents were used as received from commercial suppliers
without further purification. Thin-layer chromatography (TLC) was
performed on Macherey-Nagel Polygram syl G/UV precoated silica
gel polyester plates. The products were visualized by exposure to
UV light (254 nm), iodine vapour or submersion in cerium molyb-
date stain [aqueous solution of phosphomolybdic acid (2%),
CeSO4$4H2O (1%) and H2SO4 (6%)]. Column chromatography was
performed using 60 Å silica gel purchased from SDS. Melting points
were determined 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 the main ab-
sorption bands. 1H and 13C NMR spectra were recorded on a Bruker
AV-400 instrument at room temperature using the residual solvent
d
1.30–1.78 (m, 7H), 1.94 (m,
d
4.4. Synthesis of methyl (2S,3aS,7aS)-N-(tert-butoxy-
carbonyl)octahydroindole-2-carboxylate, (S,S,S)-4
A solution of methyl (2S,3aS,7aS)-octahydroindole-2-carboxylate
(3.76 g, 17.10 mmol) in THF (40 mL) was treated with 4-dimethyl-
aminopyridine (209 mg, 1.71 mmol) and N,N-diisopropylethylamine
(5.9 mL, 34.20 mmol). After stirring at room temperature for
30 min, di-tert-butyl dicarbonate (5.59 g, 25.65 mmol) was added.
The resulting mixture was stirred at room temperature for an ad-
ditional 24 h. The reaction mixture was diluted with diethyl ether
(150 mL) and washed with saturated aqueous NaHCO3. The aque-
ous phase was extracted with ethyl acetate several times and the
combined organic layers were dried over MgSO4 and filtered. The
solvent was concentrated in vacuo and the residue was purified by
column chromatography (eluent: hexanes/ethyl acetate 10:1) to
afford pure (S,S,S)-4 as a colourless oil (4.65 g, 16.41 mmol, 96%
signal as the internal standard; chemical shifts (d) are expressed in
parts per million and coupling constants (J) in hertz. Optical rota-
tions were measured at room temperature using a JASCO P-1020
polarimeter. High-resolution mass spectra were obtained on
a Bruker Microtof-Q spectrometer. Compounds (S,S,S)-1,6g (R,S,S)-
1,10a (S,S,S,R)-7a,10a (S,S,S,R)-7b10a and (S,S,S,S)-7c10a were prepared
according to previously reported methods.
4.2. X-ray diffraction
yield). [ 1753, 1700, 1397,
a
]
ꢀ31.8 (c 0.48, CHCl3). IR (neat)
n
D
Colourless single crystals of (R,S,S)-5c and (S,S,S)-6a were, re-
spectively, obtained by slow evaporation of ethyl acetate or
dichloromethane/ethyl acetate solutions. The X-ray diffraction data
were collected at room temperature or 150 K, respectively, on an
1169 cmꢀ1 1H NMR (DMSO-d6, 400 MHz)
. d 1.03–1.43 (m, 4H),
overlapped with 1.30, 1.37 (two s, 9H), 1.51–1.67 (m, 3H), 1.77–1.98
(m, 2H), 2.06 (m, 1H), 2.28 (m, 1H), 3.60–3.68 (m, 1H), overlapped
with 3.62, 3.65 (two s, 3H), 4.14 (m, 1H). 13C NMR (DMSO-d6,

5178
F.J. Sayago et al. / Tetrahedron 65 (2009) 5174–5180
100 MHz)
d
(duplicate signals are observed for most carbons) 19.98,
152.32; 174.37, 174.66. HRMS (ESI) C16H27NNaO4 [MþNa]þ: calcd
20.03; 23.13, 23.25; 25.18; 27.09, 27.55; 27.84, 28.04; 30.94, 31.66;
35.62, 36.23; 51.64, 51.72; 56.29, 56.77; 58.27, 58.69; 78.56; 152.19;
172.99, 173.45. HRMS (ESI) C15H25NNaO4 [MþNa]þ: calcd 306.1676,
found 306.1673.
320.1832, found 320.1832.
4.7. Synthesis of methyl (2S,3aS,7aS)-N-(tert-butoxycarbonyl)-
2-allyloctahydroindole-2-carboxylate, (S,S,S)-5b
4.5. Synthesis of methyl (2R,3aS,7aS)-N-(tert-butoxy-
carbonyl)octahydroindole-2-carboxylate, (R,S,S)-4
Using allyl bromide (247 mL, 2.86 mmol) as the alkylating agent,
an identical procedure to that described above was applied to the
transformation of (S,S,S)-4 (200 mg, 0.71 mmol) into a 90:10 mix-
ture of (S,S,S)-5b and (R,S,S)-5b (190 mg, 0.59 mmol, 83% yield).
Purification of the mixture by column chromatography (eluent:
hexanes/ethyl acetate 10:1) furnished the major isomer (S,S,S)-5b
Thionyl chloride (177 mL, 2.43 mmol) was added dropwise to an
ice-cooled solution of (2R,3aS,7aS)-octahydroindole-2-carboxylic
acid10a (241 mg, 1.17 mmol) in dry methanol (3.0 mL). The
resulting solution was stirred at room temperature for 24 h. The
solvent was concentrated in vacuo and the resulting residue was
lyophilized to afford a yellow solid, which was then dissolved in
THF (3.0 mL). This solution was treated with 4-dimethylamino-
pyridine (14 mg, 0.11 mmol) and N,N-diisopropylethylamine
as a colourless oil (162 mg, 0.50 mmol, 71% yield). [
a
]
þ28.7 (c
0.91, CHCl3). IR (neat)
(DMSO-d6, 400 MHz)
n
1743, 1694, 1389, 1178 cmꢀ1D
.
1H NMR
d
1.04 (m, 1H), 1.12–1.26 (m, 1H), 1.28–1.51 (m,
2H), overlapped with 1.32, 1.37 (two s, 9H), 1.49–1.63 (m, 3H), 1.84
(m, 1H), 1.95–2.20 (m, 2H), 2.40 (m, 1H), 2.56–2.87 (m, 2H), 3.61–
3.73 (m, 1H), overlapped with 3.62, 3.66 (two s, 3H), 5.04–5.12 (m,
(407 mL, 2.34 mmol). After stirring at room temperature for
2H), 5.81 (m, 1H). 13C NMR (DMSO-d6, 100 MHz)
d (duplicate signals
30 min, di-tert-butyl dicarbonate (383 mg, 1.76 mmol) was added.
The resulting mixture was stirred at room temperature for an
additional 24 h. The reaction mixture was diluted with diethyl
ether (10 mL) and washed with saturated aqueous NaHCO3. The
aqueous phase was extracted several times with ethyl acetate and
the combined organic layers were dried over MgSO4 and filtered.
The solvent was concentrated in vacuo and the residue was pu-
rified by column chromatography (eluent: hexanes/ethyl acetate
are observed for most carbons) 19.98, 20.11; 22.95, 23.19; 25.07,
25.15; 25.61, 26.55; 27.85, 28.01; 33.37, 34.29; 36.90, 38.09; 38.76,
40.39; 51.96, 52.11; 57.94, 58.05; 66.70, 66.93; 78.51, 78.76; 118.07,
118.20; 134.38; 151.76, 152.57; 174.09, 174.38. HRMS (ESI)
C18H29NNaO4 [MþNa]þ: calcd 346.1989, found 346.1972.
4.8. Synthesis of methyl (2R,3aS,7aS)-N-(tert-butoxy-
carbonyl)-2-benzyloctahydroindole-2-carboxylate, (R,S,S)-5c
10:1) to afford pure (R,S,S)-4 as
0.94 mmol, 80% yield). [
þ55.5 (c 0.43, CHCl3). IR (neat)
1694, 1394, 1178 cmꢀ1 1H NMR (DMSO-d6, 400 MHz)
a
colourless oil (266 mg,
1751,
1.06–1.42
a
]
n
D
.
d
Using benzyl bromide (340 mL, 2.86 mmol) as the alkylating
(m, 4H), overlapped with 1.30, 1.38 (two s, 9H), 1.45–1.70 (m, 4H),
1.84–1.99 (m, 1H), 2.24–2.35 (m, 2H), 3.60–3.75 (m, 1H), over-
lapped with 3.61, 3.64 (two s, 3H), 4.17 (m, 1H). 13C NMR (DMSO-
agent, an identical procedure to that described above was applied
to the transformation of (S,S,S)-4 (200 mg, 0.71 mmol) into
a 86:14 mixture of (R,S,S)-5c and (S,S,S)-5c (256 mg, 0.69 mmol,
97% yield). The purification of the mixture by column chroma-
tography (eluent: hexanes/ethyl acetate 10:1) furnished the major
isomer (R,S,S)-5c as a colourless solid (203 mg, 0.54 mmol, 77%
d6, 100 MHz)
d (duplicate signals are observed for most carbons)
20.00, 20.21; 22.79, 23.09; 25.04; 27.11, 27.77; 27.81, 28.01; 30.25,
31.34; 34.14, 34.91; 51.62, 51.68; 56.01, 56.30; 57.38, 57.73; 78.57,
78.60; 152.27, 153.04; 172.77, 173.26. HRMS (ESI) C15H25NNaO4
[MþNa]þ: calcd 306.1676, found 306.1679.
yield). Mp 122–124 ꢁC. [
1726, 1684, 1459, 1386, 701 cmꢀ1
0.82–0.99 (m, 2H), 1.01–1.18 (m, 2H), 1.19–1.32 (m, 2H), 1.34–1.54
a
]
D
þ91.0 (c 0.46, CHCl3). IR (Nujol)
n
.
1H NMR (DMSO-d6, 400 MHz)
d
4.6. Synthesis of methyl (2S,3aS,7aS)-N-(tert-butoxycarbonyl)-
2-methyloctahydroindole-2-carboxylate, (S,S,S)-5a
(m, 2H), overlapped with 1.40, 1.44 (two s, 9H), 1.89–2.17 (m, 3H),
2.98, 3.03 (two d, 1H, J¼13.4 Hz), 3.28 (m, 1H), 3.43, 3.58 (two d,
1H, J¼13.4 Hz), 3.67, 3.71 (two s, 3H), 7.14 (m, 2H), 7.22–7.32 (m,
3H). 13C NMR (DMSO-d6, 100 MHz)
d (duplicate signals are ob-
A 1.8 M solution of LDA in hexanes (14.2 mL, 25.56 mmol) was
added dropwise by syringe to a stirred solution of (S,S,S)-4 (3.09 g,
10.90 mmol) in anhydrous THF (57 mL) at ꢀ78 ꢁC. After stirring at
this temperature for 30 min, methyl iodide (2.8 mL, 44.10 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 and extracted with dichloro-
methane several times. The combined organic layers were dried
over anhydrous MgSO4 and filtered. The solvent was concentrated
in vacuo and the residue was filtered through a short pad of silica
gel eluting with hexanes/ethyl acetate 1:1 to afford a 89:11 mix-
ture of (S,S,S)-5a and (R,S,S)-5a (2.98 g, 10.03 mmol, 92% yield).
The purification of the mixture by column chromatography (elu-
ent: hexanes/ethyl acetate 10:1) furnished the major isomer
served for most carbons) 19.80, 19.95; 22.76, 23.01; 24.87, 24.94;
25.54, 26.47; 27.95, 28.10; 32.47, 33.36; 37.04, 38.13; 38.37, 40.07;
52.11, 52.25; 57.83, 57.85; 67.66, 67.76; 78.60, 79.03; 126.47,
126.55; 128.01, 128.08; 130.00, 130.04; 137.30, 137.35; 151.84,
152.84; 174.25, 174.54. HRMS (ESI) C22H31NNaO4 [MþNa]þ: calcd
396.2145, found 396.2151.
4.9. Synthesis of methyl (2S,3aS,7aS)-2-methyloctahydro-
indole-2-carboxylate hydrochloride, (S,S,S)-6a
A 3 N solution of HCl in anhydrous ethyl acetate (5 mL) was
added to (S,S,S)-5a (100 mg, 0.34 mmol) and the resulting mixture
was stirred at room temperature for 4 h. The solvent was concen-
trated in vacuo and the resulting white solid was lyophilized to
afford pure (S,S,S)-6a as the hydrochloride salt (75 mg, 0.32 mmol,
(S,S,S)-5a as a colourless oil (2.43 g, 8.17 mmol, 75% yield). [
þ9.5 (c 0.95, CHCl3). IR (neat) 1743, 1693, 1453, 1389, 1259,
1181 cmꢀ1. 1H NMR (DMSO-d6, 400 MHz)
1.06 (m, 1H), 1.14–1.50
a]
D
n
d
(m, 3H), overlapped with 1.30, 1.36 (two s, 9H), and with 1.43, 1.45
(two s, 3H), 1.54–1.68 (m, 4H), 1.94–2.10 (m, 1H), 2.11–2.25 (m,
1H), 2.40–2.48 (m, 1H), 3.60–3.72 (m, 1H) overlapped with 3.60,
95% yield). Mp 160–162 ꢁC. [
a
]
D
ꢀ47.7 (c 0.56, CHCl3). IR (Nujol)
n
1746, 1570, 1464, 1379 cmꢀ1. 1H NMR (CDCl3, 400 MHz)
d
1.28–1.72
(m, 7H), 1.87 (s, 3H), 2.01 (dd, 1H, J¼13.3, 7.2 Hz), 2.70 (m, 1H), 2.37
3.65 (two s, 3H). 13C NMR (DMSO-d6, 100 MHz)
d (duplicate sig-
(dd, 1H, J¼13.3, 9.9 Hz), 2.67 (m, 1H), 3.88 (s, 3H), 3.98 (m, 1H), 7.93
nals are observed for most carbons) 20.10, 20.21; 21.77, 23.13;
23.00, 23.23; 25.03, 25.11; 25.65, 26.46; 27.85, 28.01; 33.62, 34.54;
38.87, 39.97; 51.86, 52.04; 57.52, 57.68; 64.40; 78.41, 78.52; 151.66,
(m, 1H), 11.62 (m, 1H). 13C NMR (CDCl3, 100 MHz)
d 20.33, 22.27,
24.31, 24.36, 24.63, 35.81, 38.98, 53.95, 59.71, 67.20, 172.87. HRMS
(ESI) C11H20NO2 Mþ: calcd 198.1489, found 198.1497.

F.J. Sayago et al. / Tetrahedron 65 (2009) 5174–5180
5179
4.10. Synthesis of methyl (2S,3aS,7aS)-2-allyloctahydro-
indole-2-carboxylate hydrochloride, (S,S,S)-6b
IR (Nujol)
400 MHz)
n
1751, 1446, 1226, 1004 cmꢀ1
1.22–1.34 (m, 2H), 1.39–1.63 (m, 3H), 1.70–1.86 (m,
.
1H NMR (DMSO-d6,
d
3H), 1.96 (dd, 1H, J¼13.6, 8.4 Hz), 2.19 (m, 1H), 2.48 (dd, 1H,
J¼13.6, 7.2 Hz), 2.72 (dd, 1H, J¼14.0, 8.4 Hz), 2.90 (dd, 1H, J¼14.0,
6.0 Hz), 3.63 (m, 1H), 3.75 (s, 3H), 5.15–5.22 (m, 2H), 5.75 (m, 1H),
An identical procedure to that described above was applied to
the transformation of (S,S,S)-5b (100 mg, 0.31 mmol) into (S,S,S)-6b
as the hydrochloride salt (79 mg, 0.30 mmol, 98% yield). Mp 295–
9.60 (m, 2H). 13C NMR (CDCl3, 100 MHz)
d 20.62, 21.88, 25.31,
297 ꢁC (dec). [
a
]
ꢀ98.4 (c 0.44, CHCl3). IR (Nujol)
n
1752, 1552,
25.47, 35.39, 37.35, 41.67, 53.50, 59.57, 71.78, 120.34, 130.86,
170.12. HRMS (ESI) C13H22NO2 Mþ: calcd 224.1645, found
224.1649.
D
1458, 1217 cmꢀ1. 1H NMR (DMSO-d6, 400 MHz)
d
1.16–1.27 (m, 1H),
1.29–1.39 (m, 3H), 1.45–1.53 (m, 1H), 1.54–1.66 (m, 2H), 1.72–1.80
(m, 1H), 2.07 (dd, 1H, J¼13.2, 7.3 Hz), 2.36 (dd, 1H, J¼13.2, 10.8 Hz),
2.43–2.54 (m, 1H), 2.68 (dd, 1H, J¼14.2, 7.9 Hz), 2.84 (dd, 1H, J¼14.2,
6.4 Hz), 3.68 (m, 1H), 3.79 (s, 3H), 5.18–5.28 (m, 2H), 5.70 (m, 1H),
4.14. Synthesis of methyl (2S,3aS,7aS)-2-benzyloctahydro-
indole-2-carboxylate hydrochloride, (S,S,S)-6c
8.81 (m, 1H), 10.14 (m, 1H). 13C NMR (MeOD, 100 MHz)
d 21.21,
23.47, 25.31, 25.69, 37.53, 38.31, 42.59, 54.56, 61.76, 72.60, 122.25,
130.98, 173.02. HRMS (ESI) C13H22NO2 Mþ: calcd 224.1645, found
224.1643.
An identical procedure to that described above was applied to
the transformation of (S,S,S,S)-7c10a (200 mg, 0.52 mmol) into
(S,S,S)-6c, which was isolated as the hydrochloride salt (119 mg,
0.39 mmol, 75% yield). Mp 275–277 ꢁC (dec). [
CHCl3). IR (Nujol)
1749, 1460, 1377 cmꢀ1
400 MHz) 1.22–1.34 (m, 1H), 1.40–1.56 (m, 2H), 1.63–1.80 (m, 2H),
a]
þ33.4 (c 0.44,
D
n
.
1H NMR (CDCl3,
4.11. Synthesis of methyl (2R,3aS,7aS)-2-benzyloctahydro-
indole-2-carboxylate hydrochloride, (R,S,S)-6c
d
1.88–2.01 (m, 2H), 2.15 (dd, 1H, J¼13.0, 11.0 Hz), 2.23–2.40 (m, 2H),
2.53 (dd, 1H, J¼13.0, 6.6 Hz), 3.43 (d, 1H, J¼13.8 Hz), 3.74 (s, 3H),
3.87–3.98 (m, 1H), overlapped with 3.94 (d, 1H, J¼13.8 Hz), 7.24–
7.31 (m, 5H), 9.93 (m, 1H), 10.47 (m, 1H). 13C NMR (MeOD, 100 MHz)
An identical procedure to that described above was applied to
the transformation of (R,S,S)-5c (100 mg, 0.27 mmol) into (R,S,S)-6c,
which was isolated as the hydrochloride salt (80 mg, 0.26 mmol,
96% yield). Mp 301–303 ꢁC (dec). [
(Nujol)
400 MHz)
a]
ꢀ88.1 (c 0.45, CHCl3). IR
D
d
21.69, 22.21, 25.90, 26.84, 36.56, 39.79, 43.61, 54.20, 61.11, 74.68,
n
1744, 1459, 1376, 1345, 1271, 1228 cmꢀ1. 1H NMR (CDCl3,
1.23–1.40 (m, 3H), 1.42–1.57 (m, 2H), 1.61–1.74 (m, 2H),
129.08, 129.98, 130.58, 135.27, 171.75. HRMS (ESI) C17H24NO2 Mþ:
calcd 274.1802, found 274.1805.
d
2.03–2.11 (m, 1H), 2.24 (dd, 1H, J¼13.8, 7.8 Hz), 2.47 (dd, 1H, J¼13.8,
10.4 Hz), 2.87 (m, 1H), 3.36 (d, 1H, J¼14.1 Hz), 3.74 (s, 3H), 3.83 (d,
1H, J¼14.1 Hz), 4.11 (m, 1H), 7.22–7.31 (m, 3H), 7.39–7.41 (m, 2H),
4.15. Synthesis of (2S,3aS,7aS)-N-(tert-butoxycarbonyl)-2-
methyloctahydroindole-2-carboxylic acid, (S,S,S)-8a
7.99 (m, 1H), 11.62 (m, 1H). 13C NMR (CDCl3, 100 MHz)
d 20.10, 22.47,
24.53, 24.58, 35.46, 36.37, 42.93, 53.55, 60.41, 72.18, 127.87, 128.71,
129.75, 133.65, 171.69. HRMS (ESI) C17H24NO2 Mþ: calcd 274.1802,
found 274.1809.
A 1 M solution of KOH in methanol (20 mL) was added to
(S,S,S)-5a (826 mg, 2.78 mmol) and the resulting mixture was
heated under reflux for 24 h. The solvent was evaporated and the
residue was acidified with 5% aqueous KHSO3. The mixture was
extracted with dichloromethane (2ꢂ50 mL) and the combined
organic layers were dried over MgSO4 and filtered. The solvent
was concentrated in vacuo to afford pure (S,S,S)-8a as a white
4.12. Synthesis of methyl (2R,3aS,7aS)-2-methyloctahydro-
indole-2-carboxylate hydrochloride, (R,S,S)-6a
A
solution of trichloromethyloxazolidinone (S,S,S,R)-7a10a
(200 mg, 0.64 mmol) in dry methanol (10 mL) was treated with
1 M solution of sodium methoxide in methanol (1 mL,
solid (753 mg, 2.66 mmol, 92% yield). Mp 144–146 ꢁC. [
(c 0.49, CHCl3). IR (Nujol) 3500–2500, 1703, 1461, 1380,
1165 cmꢀ1 1H NMR (DMSO-d6, 400 MHz)
0.98–1.10 (m, 1H),
a]
ꢀ21.0
D
n
a
.
d
1.00 mmol). After stirring the reaction mixture at room temper-
ature for 12 h, acetyl chloride (3 mL, 42.2 mmol) was added. The
resulting suspension was stirred under reflux for an additional
24 h. The solvent was concentrated in vacuo and the resulting
residue was diluted with dichloromethane. Sodium chloride pre-
cipitated upon addition of the solvent and it was filtered off. The
solvent was concentrated under reduced pressure and the white
solid was lyophilized and washed with small portions of ethyl
acetate to afford pure (R,S,S)-6a as the hydrochloride salt (120 mg,
1.11–1.28 (m, 1H), 1.30–1.52 (m, 2H), overlapped with 1.30, 1.52
(two s, 9H) and 1.39, 1.41 (two s, 3H), 1.54–1.65 (m, 4H), 1.95, 2.05
(two m, 1H), 2.20 (m, 1H), 2.43 (m, 1H), 3.65 (m, 1H), 12.34 (br s,
1H). 13C NMR (DMSO-d6, 100 MHz)
d (duplicate signals are ob-
served for most carbons) 20.18, 20.30; 21.71, 23.16; 23.07, 23.28;
25.13, 25.20; 25.58, 26.52; 27.92, 28.11; 33.68, 34.51; 39.11, 40.11;
57.61, 57.76; 64.21, 64.31; 78.11, 78.44; 152.00, 152.23; 175.54,
176.02. HRMS (ESI) C15H24NO4 [MꢀH]ꢀ: calcd 282.1711, found
282.1705.
0.51 mmol, 80% yield). Mp 114–116 ꢁC. [
a]
þ33.8 (c 0.40, CHCl3).
D
IR (Nujol)
400 MHz)
n
1749, 1454, 1381, 1201 cmꢀ1
.
1H NMR (CDCl3,
d
1.31–1.34 (m, 1H), 1.39–1.51 (m, 2H), 1.61–1.76 (m,
Acknowledgements
2H), 1.82 (m, 1H), 1.92 (m, 1H), 1.95 (s, 3H), 2.06 (dd, 1H, J¼13.2,
10.4 Hz), 2.24 (m, 1H), 2.38 (m, 1H), 2.47 (dd, 1H, J¼13.2, 6.4 Hz),
3.86 (s, 3H), 4.04 (m, 1H), 9.33 (m, 1H), 10.48 (m, 1H). 13C NMR
´
Financial support from the Ministerio de Educacion y Ciencia–
FEDER (project CTQ2007-62245) and Gobierno de Arago´ n (pro-
ject PIP206/2005 and research group E40) is gratefully ac-
knowledged. 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 N01-CO-12400. The
content of this publication does not necessarily reflect the view
of the policies of the Department of Health and Human Services,
nor does mention of trade names, commercial products, or or-
ganization imply endorsement by the U.S. Government. This re-
search was supported (in part) by the Intramural Research
Program of the NIH, National Cancer Institute, Center for Cancer
Research.
(CDCl3, 100 MHz)
d 20.52, 22.18, 24.64, 25.17, 25.51, 36.03, 39.66,
53.89, 59.80, 68.06, 171.84. HRMS (ESI) C11H20NO2 Mþ: calcd
198.1489, found 198.1490.
4.13. Synthesis of methyl (2R,3aS,7aS)-2-allyloctahydro-
indole-2-carboxylate hydrochloride, (R,S,S)-6b
An identical procedure to that described above was applied to
the transformation of (S,S,S,R)-7b10a (200 mg, 0.59 mmol) into
(R,S,S)-6b, which was isolated as the hydrochloride salt (120 mg,
0.46 mmol, 78% yield). Mp 133–135 ꢁC. [
a
]
þ60.3 (c 0.44, CHCl3).
D

5180
F.J. Sayago et al. / Tetrahedron 65 (2009) 5174–5180
8. (a) Karoyan, P.; Sagan, S.; Lequin, O.; Quancard, J.; Lavielle, S.; Chassaing, G.
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