Practical stereoselective synthesis of conformationally constrained unnatural proline-based amino acids and peptidomimetics

Article abstract of DOI:10.1016/S0040-4020(01)00538-5

A practical synthetic scheme was developed to prepare both the cis- and trans-fused stereoisomers of N-Boc-L-octahydroindole-2-carboxylic acid (L-Oic) methyl ester. Key event of the synthetic sequence was the ring-closing metathesis of a suitable diallyla

Full text of DOI:10.1016/S0040-4020(01)00538-5

TETRAHEDRON
Pergamon
Tetrahedron 57 +2001) 6463±6473
Practical stereoselective synthesis of conformationally constrained
unnatural proline-based amino acids and peptidomimetics
Laura Belvisi,a Lino Colombo,b,p Matteo Colombo,a Marcello Di Giacomo,b Leonardo Manzoni,a
Bruno Vodopivecc and Carlo Scolasticoa,p
a
Á
Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, Centro CNR per lo studio delle Sostanze Organiche
Naturali, via G. Venezian 21, I-20133 Milano, Italy
b
Á
Dipartimento di Chimica Farmaceutica, Universita di Pavia, via Taramelli 12, I-27100 Pavia, Italy
Á
Dipartimento di Biotecnologie e Bioscienze, Universita degli Studi di Milano-Bicocca, P.zza Della Scienza 2, I-20126 Milano, Italy
c
Received 5 February 2001; revised 6 March 2001; accepted 22 March 2001
AbstractÐA practical synthetic scheme was developed to prepare both the cis- and trans-fused stereoisomers of N-Boc-l-octahydroindole-
2-carboxylic acid +l-Oic) methyl ester. Key event of the synthetic sequence was the ring-closing metathesis of a suitable diallylated proline
derivative. This is the ®rst reported practical synthesis of the trans-fused isomer. Functionalization of the octahydroindole nucleus by
electrochemical oxidation followed by acid-catalysed allylation paved the way for the preparation of reverse-turn dipeptide mimics. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
the design and synthesis of conformationally constrained
compounds that mimic or induce certain secondary
structural features of peptides and proteins.1
Biologically active peptides are involved in a great number
of physiological processes through their interaction with
receptors and enzymes. However, peptides are not ideal
drug candidates due to their low metabolic stability toward
endogenous proteases, poor oral bioavailability, rapid
excretion, and lack of selectivity towards a speci®c receptor,
due to conformational ¯exibility. These dif®culties could be
overcome by resorting to peptide analogues or de novo-
designed molecules that mimic the bioactive conformation
and the action of the native peptides at the receptor level.
These molecules, called peptidomimetics, should display
high receptor af®nity and selectivity, in addition to
enhanced bioavailability and metabolic stability. In the
®eld of peptidomimetics much effort has been focused on
Since reverse-turn motifs are implicated as recognition
elements in a variety of biological interactions, the design
of small constrained mimetics of turn structures is of great
importance to medicinal chemistry. This goal has been
frequently achieved by replacing reverse-turn dipeptide
motifs with constrained molecules that reproduce their
conformational features. In that regard, a particularly attrac-
tive class of compounds are fused bicyclic systems,2 and in
particular the 1-aza-2-oxobicyclo[X.Y.0]alkane amino
acids. Owing to their rigid geometry, these scaffolds are
also useful tools to probe and elucidate structure±activity
relationships.
Scheme 1. Synthetic scheme leading to 1-aza-2-oxobicyclo[X.3.0]alkane amino acids of general formula I.
Keywords: ring-closing metathesis; unnatural amino acids; octahydroindole ring; peptidomimetics.
Corresponding authors. Tel.: 139-0382-507387; fax: 139-0382-422975; e-mail: Lino.Colombo@unipv.it;
p
tel.: 139-02-2367593; fax: 139-02-2663079; e-mail: Carlo.Scolastico@unimi.it
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+01)00 538-5

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L. Belvisi et al. / Tetrahedron 57 22001) 6463±6473
constrained, proline-based unusual amino acid has been
proved to be successful in mapping the unknown topology
of peptide receptors and in developing potent receptor
antagonists. For example, a number of bradykinin B2 recep-
tor antagonists have been reported that contain nonproteino-
genic amino acid pair X-l-Oic, forcing a b-turn into the
backbone when positioned, respectively, at the i11 and
i12 positions of the turn.5 However, the high cost of this
amino acid, its relevance in the synthesis of bioactive
compounds and the availability of only one isomer
convinced us to investigate a synthetic sequence, which
could start from inexpensive and commercially available
products, to synthesize different stereoisomers of octahydro-
indole derivatives.
Figure 1. Commercially available octahydroindole-2-carboxylic acid
derivatives 1 and 2 and the trans isomer 3.
In this paper, we report on a convenient method for the
synthesis of both cis- and trans-fused stereoisomers of
N-Boc-l-octahydroindole-2-carboxylic acid methyl ester
2 and 3 +Fig. 1), which could be inserted as sterically
restricted unnatural residues in biologically active
sequences to study both structural and biological
properties.
Figure 2. Trinuclear dipeptide mimics of general formula II.
In the course of our studies on peptide secondary structure
mimics, we have synthesized several 5,5- 6,5-, 7,5- and
8,5-fused 1-aza-2-oxobicyclo[X.3.0]alkane amino acids
+Scheme 1, general formula I),3 that can be regarded as
conformationally restricted substitutes for X-Pro dipeptide
units. All these bicyclic lactams include a natural l-Pro
residue, but vary in the lactam ring size, and in the con-
®guration at the fusion carbon atom and at the NH2-bearing
carbon. The conformational properties of these proline-
derived bicyclic lactams have been investigated by a combi-
nation of computational and spectroscopic techniques, to
assess their propensities to mimic the reverse-turn peptide
motif.4 These studies have revealed that these bicyclic
scaffolds can mimic reverse-turn motifs, although there is
a dependence of the turn-inducing ability on lactam ring size
and stereochemistry. Reverse-turn mimetic bicyclic lactams
have been shown to exhibit a tendency to form an inverse
g-turn or a type II0 b-turn.
Functionalization of the octahydroindole nucleus by electro-
chemical oxidation and its conversion into reverse-turn
dipeptide mimics of general formula II +Fig. 2) is also
described in the paper.
2. Results and discussion
The current literature methods for obtaining 2-carboxyocta-
hydroindole derivatives are based on the use of tyrosine
compounds as starting materials.6 Although cis-fused octa-
hydroindol-6-one derivatives are achievable in multigram
amounts and good yields, the trans-fused stereoisomers
are not attainable by the same methodology. As mentioned
above one stereoisomer of N-Boc-l-octahydroindole-2-
carboxylic acid +N-Boc-l-Oic) 1 is commercially available
but its ring junction is cis as well +Fig. 1).
The possibility of functionalizing these molecules with lipo-
philic appendages is very attractive because they could
improve peptide-receptor af®nity by interacting with hydro-
phobic pockets. To this end, commercially available
unnatural amino acid N-Boc-l-octahydroindole-2-carb-
oxylic acid +N-Boc-l-Oic) 1 +Fig. 1) was recognized as a
different, suitable starting point for azabicycloalkane synth-
esis. Substitution of hydrophobic residues in critical regions
of biologically active peptides by this conformationally
Therefore the synthesis of trans-fused derivatives could be
of signi®cant interest, both because of the challenge
inherent with the stereoselective formation of the trans
junction, and because such compounds, when inserted into
peptide chains, may induce conformational patterns differ-
ent from those originated by the cis counterparts. Here we
report on a method for the stereoselective synthesis of
Scheme 2. Retrosynthetic analysis of compound 3.

L. Belvisi et al. / Tetrahedron 57 22001) 6463±6473
6465
Scheme 3. i: HMDS, BuLi, allyl bromide, THF, 72%; ii: TFA, CH2Cl2, 08C; iii: toluene, 1108C, 85% over two steps; iv: Boc2O, DMAP, THF, 98%; v:
LiEt3BH, THF, 2788C, 91%; vi: Allyl tributyltin, tert-butyldimethylsilyl tri¯uoromethanesulphonate, 2788C, 75%; x: Grubbs catalyst, CH2Cl2, 91%; xi: H2,
Pd/C, EtOH, 95%.
the unknown trans-fused N-Boc-l-octahydroindole-2-
carboxylic acid methyl ester +N-Boc-l-Oic-OMe) 3. The
retrosynthetic analysis of 3 is depicted in Scheme 2. The
key events for the synthesis are the ring-closing metathesis
of the diallylated proline derivative 4 and the allylation of
the N-acyliminium ion derived from the hemiaminal 5.
Nucleophilic addition of the allyl unit could be anticipated
to occur predominantly on the opposite side of the adjacent
allyl substituent thus providing the desired 4,5-trans diallyl
derivative 4.
best performed by the use of lithium triethylborohydride at
2788C. According to ample literature precedent and our
own experience on similar substrates,8 hemiaminal 9 was
®rst converted to the corresponding methoxy derivative 5,
which should be a more suitable substrate for the following
acid-catalysed allylation reaction. Brief treatment of 9 with
a methanol solution of excess trimethyl orthoformate in the
presence of catalytic pyridinium tosylate gave 5 in 94%.
However, despite several attempts using either allyltri-
butyltin or allyltrimethylsilane in the presence of various
Lewis acids, in all cases the allylated product 4 was formed
in unacceptably low yields. Suspecting that the scarce reac-
tivity of the methoxylated substrate was to ascribe primarily
to the inef®cient formation of the intermediate N-acyli-
minium ion, we tried to raise the reaction rate by switching
to a better leaving group. Support for this hypothesis came
from the behaviour of the thiophenyl derivative 10, which
did not react at all, the sul®de moiety being a poor leaving
group. In contrast, replacement of the methoxy by an
acetoxy substituent was shown to be particularly bene®cial
in the subsequent allylation reaction. The best yielding
conditions required a twofold excess of allyltributyltin
and tert-butyldimethylsilyl tri¯uoromethanesulphonate.
Eventually we discovered that the aminal 9 itself could be
allylated in the same conditions and almost the same yield
as the acetoxy derivative 11, thus making the synthetic
sequence one step shorter. The diallyl product was obtained
as a mixture of trans and cis isomers 4-trans and 4-cis in
a 3:1 ratio, as determined by NMR analysis of the crude
The starting material for the synthesis was the N-Boc-
protected dimethyl glutamate 6, which was converted into
the 4-allyl pyroglutamic ester 8 following a four-step
synthetic pathway reported in a recent communication,7
and summarized in Scheme 3.
Treatment of the Li-enolate of 6 with allyl bromide afforded
the 4-+S)-allyl derivative 7 in good yield and almost
complete stereoselectivity +.98:2). This, in turn, was
N-deprotected with tri¯uoroacetic acid and thermally
cyclized to the corresponding pyroglutamate. Reprotection
of the lactam as an N-Boc derivative using standard con-
ditions led to the pyroglutamate 8. Attempts to shorten the
synthetic sequence by directly cyclizing the N-carbamate
anion of 7, thus avoiding the deprotection and reprotection
steps, gave unsatisfactory results.
Selective reduction of the imide 8 to the hemiaminal 9 was

6466
L. Belvisi et al. / Tetrahedron 57 22001) 6463±6473
Scheme 4. i: CH3I, KHCO3, DMF, 99%; ii: anodic oxidation, Me4NBF4, NaHCO3, CH3CN, MeOH, 84%; iii: allyltributyltin, BF3´Et2O, CH2Cl2, 2788C, 97%;
iv: TFA, CH2Cl2, 89%; v: KHCO3, benzyl chloroformiate, EtOAc/H2O 1:1, 99%; vi: LiOH, dioxane, 508C, 100%; vii: N,N-dimethylformamide di-tert-butyl
acetal, benzene, 92%; viii: OsCl3, Me3NO´2H2O, acetone/H2O 8:1, NaIO4, 93%.
reaction mixture and also by the relative mass balance of
the pure isomers isolated by ¯ash chromatography. Con-
®gurational assignments were postponed to the achievement
of the ®nal products whose comparison with N-Boc-l-Oic-
OMe 2 will give an immediate answer to their stereo-
chemical identity.
+Fig. 2), functionalization of Oic by electrochemical oxi-
dation10 of 2 and 3 was attempted. These studies revealed
that the trans isomer 3 gives, under the standard conditions
used for proline, a mixture of methoxylated regioisomers in
low yields. In contrast, compound 2 can be regioselectively
methoxylated by electrochemical oxidation in CH3CN/
MeOH to give a mixture of stereoisomeric 7a-methoxy-
octahydroindole derivatives 14 in 84% yield +Scheme 4).
From 14 the required aldehyde 17 was obtained as described
in Scheme 4. Thus, compound 14 was submitted to allyl-
ation with allyltributyltin in the presence of an appropriate
Lewis acid +BF3´Et2O, 97%) in anhydrous CH2Cl2 affording
compound 15 as the only isomer. Proline allylation via
N-acyl iminium ion has been studied intensively,8 and
found to occur with modest selectivity +typically 3:1) in
favour of the cis isomer. The much higher selectivity
observed in the allylation of 14 could be rationalized by
taking into account the conformation of the intermediate
N-acyl iminium ion, which was calculated by molecular
mechanics.11 Inspection of the structure shown in Fig. 3
reveals that the ion should adopt a concave shape that
should preclude nucleophilic attack from the b face.
However, one must be aware of the inadequacy of drawing
stereochemical conclusions on the course of a reaction from
the molecular mechanics ground state conformation of a
charged intermediate. In any case, the stereochemistry of
the newly formed stereocentre was determined by NOE
experiments. The cis-fusion arrangement was evidenced
by the presence of NOEs between the allylic moiety protons
and H-3a, as shown in Fig. 4. Absence of epimerization at
the other stereogenic centres during allylation was
The ring-closing metathesis of the separate stereoisomers
4-trans and 4-cis proceeded uneventfully in less than a
hour at room temperature by the action of 10% of the
Grubbs catalyst9 13 +.90% yield). The resulting ole®ns
12-trans and 12-cis were hydrogenated with 5% Pd on
charcoal affording the ®nal stereoisomeric product 3 and
1
2, respectively. Comparison of spectroscopic data +IR, H
and 13C NMR) between our ®nal compounds and the
methylester 2, derived from commercial N-Boc-l-Oic-OH
1 +Scheme 4), showed unequivocally their stereochemical
patterns as those indicated in Scheme 3.
The protocol we have developed for the construction of
proline-based bicyclic lactam dipeptide mimics3e +Scheme
1) is based on a Horner±Emmons ole®nation on a suitably
protected aldehyde followed by double-bond reduction and
cyclization. In order to exploit the octahydroindole nucleus
in this sequence for the synthesis of dipeptide mimics II
Figure 3. Molecular mechanics conformer +AMBERp force ®eld) of the
intermediate N-acyl iminium ion leading to 15.
Figure 4. NOE contacts observed for compound 15.

L. Belvisi et al. / Tetrahedron 57 22001) 6463±6473
6467
Scheme 5. i: Z-+a)-phosphonoglycine trimethyl ester, tBuOK, CH2Cl2, 2788C, 85%; ii: Boc2O, DMAP, THF, 88%; iii: H2, Pd/C 10%, MeOH; iv: toluene,
re¯ux, 85% over two steps.
con®rmed by NOE between H-2 and H-3a. Compound 16
was obtained from 15 by protecting group manipulation,
which consists of an exchange of ZN-Boc with ZN-Cbz
and ZCOOMe with ZCOOt-Bu. These transformations
were performed with the aim of preparing orthogonally
protected intermediates. Deprotection of the N-Boc group
of 15 with TFA followed by N-Cbz reprotection gave the
benzyloxycarbonyl derivative, which was hydrolysed to the
corresponding carboxylic acid and subsequently treated
with dimethylformamide di-t-butylacetal affording the
suitably protected compound 16 in 81% overall yield over
four steps. Dihydroxylation of 16 with OsCl3, Me3NO in 8:1
acetone/water, followed by NaIO4 cleavage of the inter-
mediate diols gave the aldehyde 17 in 93% yield.
Horner±Emmons ole®nation of 17 with the potassium
enolate of +^)-Z-a-phosphonoglycine trimethyl ester12
+Scheme 5) set up the complete framework of the ®nal
product in 85% yield. Treatment of 18 with Boc2O and
subsequent unselective hydrogenation of the protected
Figure 5. Dipeptide mimics 22 and 23 used in computer modelling.
Figure 6. Low-energy conformers +AMBERp force ®eld) calculated for dipeptide mimic 22.

6468
L. Belvisi et al. / Tetrahedron 57 22001) 6463±6473
compound 19 +H2, Pd/C) followed by re¯uxing in toluene
gave a 1:1 mixture of easily separable 20 and 21.13
dioic acid dimethyl ester *7). A solution of hexamethyl-
disilazane +3.96 ml, 17.50mmol) in dry THF +17 ml) under
nitrogen was treated with n-butyllithium +1.6 M solution in
n-hexane, 10.9 ml) at 08C for 10min. After cooling to
2788C, a solution of 6 +2302 mg, 8.36 mmol) in dry THF
+33 ml) was added dropwise by syringe and the resulting
pale yellow solution stirred at the same temperature for
45 min. Then freshly distilled allyl bromide was added
and the reaction mixture stirred for 3.5 h. A 10% HCl
Computational studies designed to investigate the ability
of the newly synthesized dipeptide mimics to adopt
reverse-turn conformations were performed on the model
compounds 22 and 23 +Fig. 5), following the protocol
previously employed in the study of other azabicycloalkane
amino acids.4,11 Monte Carlo molecular mechanics confor-
mational searches revealed that only mimic 22, having the
carboxy and the amino groups on the same face of the
bicyclic system, is an effective turn-inducer, promoting
either an inverse g-turn or a type II0 b-turn through intra-
molecular hydrogen bonding. The only two conformers
calculated in vacuo for compound 22 within 2 kcal/mol of
the global minimum are given in Fig. 6.
aqueous solution +10ml), saturated brine +20ml) and Et O
2
+50ml) were added, and the aqueous phase extracted with
2£30ml of Et 2O. The organic layers were collected, dried
with Na2SO4 and evaporated to dryness giving an oily resi-
due that was ¯ash chromatographed +hexanes/EtOAc 7:3) to
afford 7 +1906 mg, 6.05 mmol, 72%) as a colourless oil. 1H
NMR +300 MHz, CDCl3) d 1.44 +s, 9H), 1.95±2.04 +m, 2H),
2.34 +m, 2H), 2.58 +quintet, Jˆ6.9 Hz, 1H), 3.67 +s, 3H),
3.73 +s, 3H), 4.35 +ddd, J1ˆJ2ˆ7.8 Hz, 1H), 4.96 +d, Jˆ
7.8 Hz, 1H), 5.02±5.13 +m, 2H), 5.63±5.78 +m, 1H); 13C
NMR +75.4 MHz, CDCl3) d 28.2, 34.6, 37.3, 42.7, 52.6,
53.0, 53.3, 80.9, 118.6, 135.3, 156.3, 173.7, 176.4;
IR +liquid ®lm) 3370, 1737, 1511, 1367, 1168, 1050,
919 cm21; Elemental analysis for C15H25NO6: Calculated:
C, 57.13; H, 7.99; N, 4.44; Found: C, 57.24; H, 8.00; N,
4.43; MS: m/e +rel. intensity): 316 +1), 256 +18), 228 +3), 215
+7), 200 +38), 184 +15), 168 +7),156 +75), 139 +4), 124 +25),
114 +3), 96 +17), 82 +9), 67 +3), 57 +100).
In summary, we have reported a convenient synthetic route
for the preparation of a novel, conformationally constrained,
unnatural amino acid, the trans-fused N-Boc-l-octa-
hydroindole-2-carboxylic acid methyl ester 3. By the same
sequence the cis-fused l-Oic derivative 2 can also be
obtained, although as the minor stereoisomer. This is the
®rst known synthesis of the trans l-Oic and it will allow
studying the effect of this residue on both the structural and
biological properties of bioactive peptides. Regioselective
functionalization of the octahydroindole nucleus has been
successfully performed on the cis-fused isomer by an
electrochemical oxidation reaction that occurs selectively
at the 7a position. The 7a-methoxy derivative allowed the
synthesis of novel trinuclear dipeptide mimics, which may
improve peptide-receptor af®nity by interacting with hydro-
phobic pockets.
3.1.2. *2S,4S)-4-Allyl-5-oxopyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester 2-methyl ester *8). TFA +7 ml)
was added under nitrogen to a solution of 7 +2580mg,
8.19 mmol) in CH2Cl2 at 08C and the resulting pale yellow
solution stirred at the same temperature for 90min. After
evaporation to dryness, the oily light brown residue was
treated with aqueous Na2CO3 and extracted with EtOAc
+3£20ml). TLC analysis showed the presence of only one
spot +Rf 0.52, AcOEt/MeOH 95:5). After drying and
evaporation of the solvent TLC analysis showed that part
of the product was converted into a new compound +Rf 0.55,
AcOEt/MeOH 95:5) that was recognized as the cyclized
product. To complete the cyclization the crude reaction
mixture was dissolved in toluene +35 ml) and heated at
1108C for 40min. Evaporation of the solvent and puri®-
cation by ¯ash chromatography +EtOAc) gave 4-allyl-5-
oxopyrrolidine-2-carboxylic acid tert-butyl ester as a
colourless oil +1273 mg, 85%). 1H NMR +300 MHz,
CDCl3) d 1.17±1.93 +m, 1H), 2.06±2.21 +m, 1H), 2.46±
2.63 +m, 3H), 3.74 +s, 3H), 4.19 +t, Jˆ7.8 Hz, 1H), 5.00±
5.03 +m, 1H), 5.03±5.09 +m, 1H), 5.65±5.80 +m, 1H); 13C
NMR +75.4 MHz, CDCl3) d 30.2, 34.8, 40.5, 52.3, 53.6,
117.0, 134.8, 172.2, 178.4; IR +liquid ®lm) 3240, 1744,
1706, 1382, 1217, 1116, 1024, 921 cm21; Elemental analy-
sis for C9H13NO3: Calculated: C, 59.00; H, 7.15; N, 7.65;
Found: C, 59.12; H, 7.16; N, 7.64; MS: m/e +rel. intensity)
183 +13), 182 +40), 153 +1), 124 +100), 106 +3), 96 +41), 81
+45), 67 +7), 59 +13), 55 +10), 41 +17).
3. Experimental
3.1. General
Proton NMR spectra were recorded on Bruker AC-200 or
AC-300 spectrometers. Proton chemical shifts are reported
in parts per million +ppm) relative to internal tetramethyl-
silane and the coupling costants in hertz +the usual abbrevia-
tions are used: sˆsinglet, dˆdoublet, tˆtriplet, qˆquartet,
mˆmultiplet). Carbon NMR spectra were recorded on
Bruker AC-200 +50.3 MHz) or AC-300 +75.4 MHz) spectro-
meters; carbon chemical shifts are reported in ppm relative
to TMS. NMR data were collected at 300 K, unless other-
wise indicated. Elemental analyses were performed with a
Perkin±Elmer 240instrument. Mass spectra were obtained
with a VG 7070 EQ spectrometer. Melting points were
determined on a Stuart Scienti®c SMP3 melting point
apparatus. Optical rotations were measured in 1 dm path-
length cells of 1 ml capacity by using a Perkin±Elmer 241
polarimeter. Thin-layer chromatography +TLC) was carried
out using Merck precoated silica gel F-254 plates. Flash
chromatography was carried out with Macherey±Nagel
Silica Gel 60, 230±400 mesh. Solvents were dried using
standard procedures and reactions requiring anhydrous
conditions were performed under an argon or nitrogen
atmosphere.
Di-tert-butyl dicarbonate +1880mg, 8.60mmol) and DMAP
+30mg) were added to a solution of 4-allyl-5-oxopyrro-
lidine-2-carboxylic acid tert-butyl ester +1200 mg, 6.55
mmol) in distilled THF +20ml) at room temperature.
After stirring for 120min, the solvent was evaporated to
dryness and the crude oily product ¯ash chromatographed
3.1.1. *2S,4S)-2-Allyl-4-tert-butoxycarbonylamino-pentane-

L. Belvisi et al. / Tetrahedron 57 22001) 6463±6473
6469
+hexanes/EtOAc 7:3) to give 8 +1820mg, 98%) as colour-
less needles. Mp: 54±568C +n-pentane±Et2O); H NMR
oil which was chromatographed to afford 4-trans +colour-
less oil, 998 mg, 56%), 4-cis +colourless oil 332 mg, 19%).
1
+300 MHz, CDCl3) d 1.50+s, 9H), 1.73 +ddd, Jˆ6.9 Hz,
Jˆ6.9 Hz, Jˆ13.7 Hz, 1H), 2.15±2.29 +m, 1H), 2.48 +ddd,
Jˆ8.7 Hz, Jˆ8.7 Hz, Jˆ13.7, 1H), 2.59±2.70+m, 2H), 3.78
+s, 3H), 4.51 +dd, Jˆ8.7 Hz, Jˆ7 Hz, 1H), 5.03±5.08 +m,
1H), 5.09±5.11 +m, 1H), 5.66±5.82 +m, 1H); 13C NMR
+75.4 MHz, CDCl3) d 26.5, 27.7, 34.8, 41.8, 52.2, 57.1,
83.4, 117.5, 134.3, 149.0, 171.8, 174.1; IR +nujol) 1773,
1741, 1335, 1310, 1286, 1258, 1200, 1185, 1124, 1051,
997, 961, 915, 788 +cm21); Elemental analysis for
C14H21NO5: Calculated: C, 59.35; H, 7.47; N, 4.94;
Found: C, 59.29; H, 7.48; N, 4.95; MS, m/e +rel. intensity)
283 +39), 196 +4), 183 +53), 168 +15), 124 +100), 115 +1), 96
+4), 81 +13), 67 +3), 57 +82).
1
4-trans: H NMR +300 MHz, CDCl3) +mixture of confor-
mers) d 1.40+s, 5.4H), 1.48 +s, 3.6H), 1.72±1.81 +dt,
Jˆ3.2 Hz, Jˆ13.5 Hz, 1H), 1.98±2.18 +m, 2H), 3.72 +s,
2H), 3.73 +s, 1H), 3.60±3.73 +m, 0.7H), 3.76±3.83 +m,
0.3H), 4.21 +dd, Jˆ3.5 Hz, Jˆ9.9 Hz, 0.7H), 4.28 +dd, Jˆ
3.3, Jˆ10.0, 0.3H), 4.91±5.12 +m, 4H), 5.57±5.82 +m, 2H).
13C NMR +75.4 MHz, CDCl3) +mixture of conformers) d
28.2, 28.4, 31.8, 32.9, 37.1, 38.0, 38.4, 40.5, 41.6, 51.8,
51.9, 58.9, 59.3, 62.9, 63.0, 79.8, 80.0, 116.6, 116.7,
117.7, 117.8, 134.3, 134.4, 136.3, 136.4, 153.4, 154.1,
173.2, 173.8; IR +liquid ®lm) 3077, 1753, 1698 cm21
;
Elemental analysis for C17H27NO4: Calculated: C, 65.99;
H, 8.80; N, 4.53; Found: C, 66.18; H, 8.83; N, 4.52; MS
m/e +rel. intensity) 268 +M1ZCH2CHyCH2) +12), 208 +4),
194 +4), 168 +100), 150 +3), 108 +10), 88 +2), 81 +11), 68 +4),
57 +47).
3.1.3. *2S,4S,5S) and *2S,4S,5R)-4,5-Diallyl-pyrrolidine-
1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester *4-
cis, 4 -trans). A 1 M solution of lithium triethylborohydride
in THF +6.60ml, 6.60mmol) was added dropwise by
syringe to a dry THF solution +30ml) of 8 +1703 mg,
6.01 mmol) under nitrogen at 2788C. After stirring for
60min, a saturated NH 4Cl solution and Et2O +30ml) was
added. The separated aqueous phase was extracted with
Et2O +2£20ml) and the organic layers collected, dried
+Na2SO4) and evaporated to dryness giving a pale yellow
oil +2130mg). This product was pure enough to be
submitted to the next reaction without chromatographic
puri®cation. For the sake of characterization, a sample of
the crude reaction mixture +82 mg) was puri®ed by ¯ash
chromatography +hexanes/EtOAc 65:35) to give a diastereo-
meric mixture of 9 as a colourless oil +60mg, 91%). 1H
NMR +300 MHz, CDCl3) d 1.42 +s, 5H), 1.48 +s, 3H),
1.70±1.92 +m, 1H), 2.02±2.22 +m, 2H), 2.28±2.46 +m,
2H), 2.69 +bs, 0.3H, exchanges with D2O), 2.96 +bs, 0.7H,
exchanges with D2O), 3.75 +s, 2H), 3.76 +s, 1H), 4.19 +dd,
Jˆ7.6 Hz, Jˆ9.8 Hz, 0.7H), 4.29 +dd, Jˆ8.0Hz, Jˆ9.4 Hz,
0.3H),4.97±5.15 +m, 2H), 5.32 +d, Jˆ4.2 Hz, 0.3H), 5.44 +d,
Jˆ4.5, 0.7H), 5.73±5.89 +m, 1H). 13C NMR +75.4 MHz,
CDCl3) +mixture of diastereisomers and conformers) d
26.7, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 31.0, 31.9,
32.5, 32.8, 33.5, 34.9, 35.7, 38.3, 40.0, 42.0, 42.7, 43.0,
43.7, 44.0, 44.1, 44.8, 51.9, 52.1, 52.3, 52.6, 57.2, 58.4,
59.9, 80.1, 80.9, 81.0, 81.9, 82.1, 83.6, 84.1, 86.3, 86.7,
116.0, 116.1, 116.8, 117.5, 120.2, 121.0, 130.8, 131.3,
134.4, 135.5, 135.7, 136.0, 149.2, 153.1, 153.5, 154.1,
171.8, 172.8, 173.1, 173.3, 173.7, 174.0, 174.3, 175.3;
IR +liquid ®lm) 3465, 1753, 1740, 1696, 1366, 1258,
1199, 1167, 1137 cm21; MS, m/e +rel. intensity) 226
+M1ZCO2CH3) +21), 212 +1), 198 +1), 184 +7), 170+49),
149 +3), 126 +63), 117 +6), 108 +20), 97 +3), 81 +23), 69 +6),
57 +100), 41 +22).
4-cis: 1H NMR +300 MHz, CDCl3) +mixture of conformers)
d 1.57±1.81 +m, 1H), 2.0±2.17 +m, 1H), 2.17±2.44 +m, 5H),
3.73 +s, 1H), 3.92±4.13 +m, 1H), 4.13±4.32 +m, 1H), 4.95±
5.19 +m, 4H), 5.59±5.86 +m, 1.2H), 5.86±6.09 +m, 0.8H);
13C NMR +75.4 MHz, CDCl3) +mixture of conformers) d
28.2, 28.3, 33.5, 33.6, 33.7, 34.4, 35.0, 35.1, 41.6, 42.3,
51.8, 52.0, 58.6, 59.2, 59.3, 59.7, 79.8, 80.1, 116.0, 116.1,
116.2, 117.7, 117.8, 136.2, 136.3, 153.6, 154.3, 173.5,
173.7; IR +liquid ®lm) 3075, 1735, 1643 cm21; Elemental
analysis for C17H27NO4: Calculated: C, 65.99; H, 8.80; N,
4.53; Found: C, 66.12; H, 8.83; N, 4.54;
3.1.4. *2S,3aS,7aS) and *2S,3aS,7aR)-2,3,3a,4,7,7a-Hexa-
hydroindole-1,2-dicarboxylic acid 1-tert-butyl ester
2-methyl ester *12-cis, 12-trans). To a solution of 4-trans
+732 mg, 2.37 mmol) in dry CH2Cl2 +60ml) under nitro-
gen was added benzylidene-bis+tricyclohexylphosphine)
dichlororuthenium +195 mg, 0.24 mmol). After stirring at
room temperature for 30min, TLC analysis +hexanes/
EtOAc 85:15) showed that the reaction had gone to com-
pletion. Pb+OAc)4 +160mg) 14 was added and the solution
stirred overnight. The solvent was evaporated and the crude
mixture ¯ash chromatographed to give 12-trans +606 mg,
91%). The same procedure was adopted for the conversion
of 4-cis +302 mg, 0.98 mmol) into 12-cis +244 mg, 89%).
1
12-trans: H NMR +300 MHz, CDCl3) +mixture of confor-
mers) d 1.40+s, 5.4H), 1.47 +s, 3.6H), 1.71±2.16 +m, 7H),
2.21±2.34 +m, 1H), 2.34±2.48 +m, 1H), 2.85±2.99 +m,
0.4H), 3.08±3.23 +m, 0.6H), 3.24±3.42 +m, 1H), 3.74 +s,
3H), 4.23±4.38 +m, 1H), 5.67 +s, 2H); 13C NMR +75.4
MHz, CDCl3) +mixture of conformers) d 28.2, 28.3, 30.2,
30.4, 32.3, 33.1, 34.2, 34.9, 41.3, 42.0, 51.8, 51.9, 59.5,
59.9, 60.0, 60.3, 79.7, 80.1, 125.7, 125.8, 125.9, 126.1,
153.5, 154.6, 173.7, 174.1; IR +liquid ®lm) 3024, 1752,
1707, 1364, 1196, 1178, 1159, 1129 cm21; Elemental analy-
sis for C15H23NO4: Calculated: C, 64.04; H, 8.24; N, 4.98;
Found: C, 64.10; H, 8.24; N, 4.97; MS m/e +rel. intensity)
281 +2), 265 +84), 222 +3), 193 +1), 179 +87), 166 +72), 139
+1), 122 +100), 120 +8), 95+2), 91 +1), 78 +4), 68 +5), 57 +82).
The crude product deriving from the previous reaction
+2048 mg) was dissolved in CH2Cl2 +30ml) and added drop-
wise by syringe to a CH2Cl2 solution +5 ml) of allyltributyl-
tin +3.72 ml, 12.0mmol) and tert-butyldimethylsilyl tri-
¯uoromethanesulphonate +2.76 ml, 12.0mmol) at 2788C
under nitrogen. After stirring for 40min a saturated aqueous
solution of NaHCO3 +30ml) was added, the organic phase
separated, and the aqueous layer extracted with CH2Cl2
+2£30ml). The organic phases were collected, dried
+Na2SO4) and evaporated to dryness giving a pale yellow
1
12-cis: H NMR +300 MHz, CDCl3) +mixture of confor-
mers) d 1.41 +s, 6 H), 1.47 +s, 3H), 1.64±1.91 +m, 1H),

6470
L. Belvisi et al. / Tetrahedron 57 22001) 6463±6473
1.91±2.11 +m, 1H), 2.11±2.48 +m, 4H), 2.48±2.74 +m, 1H),
3.73 +s, 3H), 3.85±4.07 +m, 1H), 4.16±4.38 +m, 1H),5.54±
5.72 +m, 2H); 13C NMR +75.4 MHz, CDCl3) +mixture of
conformers) d 25.6, 25.7, 26.8, 27.1, 28.2, 28.4, 34.3,
34.4, 34.9, 35.2, 51.9, 52.0, 53.2, 53.6, 58.4, 59.0, 79.6,
79.7, 123.2, 123.4, 123.8, 124.1, 153.2, 153.9, 173.4,
173.8; IR +liquid ®lm) 3023, 1747, 1695, 1395, 1365,
3.1.7. *2S,3aS,7aR,S)-7a-Methoxyoctahydroindole-1,2-
dicarboxylic acid 1-tert-butyl ester 2-methyl ester *14).
In a water-cooled cell was placed 2 +438.3 mg, 1.55 mmol),
dry CH3CN/MeOH 7:3 +140ml), Me 4NBF4 +3.3 g) and
NaHCO3 +6.9 g). The stirred solution was electrolysed
using a Pt foil anode +9£4 cm) and a Pt wire cathode at a
constant current of 120mA. The reaction progress was
determined by removing 1 ml aliquots, evaporating them,
transferring the organic material with Et2O in a clean ¯ask,
evaporating the solvent and determining the ratio of reactant
methyl ester +3.75 ppm) to product methyl esters +3.8 ppm)
by NMR. When the reaction was complete +after passage of
0.19 F/mol) the suspension was ®ltered over paper washing
the ®ltered solid with Et2O and evaporating the collected
solution. The crude material was dissolved in H2O +70ml),
extracted with Et2O and the organic phase dried over
Na2SO4, ®ltered and evaporated. The crude was puri®ed
by ¯ash chromatography +hexane/EtOAc 8:2) yielding
409.2 mg +84%) of 14 as a colourless oil in an indetermin-
able diastereoisomeric mixture. 1H NMR +300 MHz,
CDCl3) d 1.40+2s, 9H), 1.0±2.55 +m, 11H) 3.30+2s, 3H),
3.70+2s, 3H), 3.85 +m, 1H); 13C NMR +50.3 MHz, CDCl3):
d 20.3, 20.4, 20.5, 23.2, 23.5, 25.3, 25.5, 25.8, 26.6, 27.0,
28.2, 33.8, 34.5, 39.4, 39.7, 40.6, 41.0, 50.7, 52.1, 52.5,
53.1, 57.7, 58.8; Elemental analysis for C16H27NO5: Calcu-
lated: C, 61.32; H, 8.68; N, 4.47; Found: C, 61.58; H, 8.88;
N, 4.40; MS +FAB1): M1ˆ313.
1172, 1143, 1106 cm21
;
Elemental analysis for
C15H23NO4: Calculated: C, 64.04; H, 8.24; N, 4.98;
Found: C, 63.97; H, 8.23; N, 4.99.
3.1.5. *2S,3aS,7aS) and *2S,3aS,7aR)-Octahydroindole-
1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
*2, 3). To a solution of 12-trans +592 mg, 2.11 mmol) in
EtOH +40ml) was added palladium, 5 wt% on activated
carbon +120mg), and the mixture was hydrogenated in a
Parr apparatus under 2 atm of H2 for 30h. The suspension
was ®ltered on Celite and the solvent evaporated to dryness
to give 3 +white solid, 566 mg, 95%). The same procedure
was adopted for the hydrogenation of 12-cis +213 mg) to 2
+white solid, 202 mg, 94%).
22
1
2: [a]D ˆ232.7 +cˆ1.21, CHCl3); H NMR +300 MHz,
CDCl3) d 1.45 +s, 9H), 0.8±2.1 +m, 10H), 2.10 +m, 1H),
3.55 +s, 3H), 3.60+m, 1H), 4.50 +m, 1H);
13C NMR
+75.4 MHz, CDCl3) +mixture of conformers): d 20.3, 23.4,
25.6, 27.2, 27.6, 28.0, 28.2, 31.4, 32.2, 36.2, 36.8, 51.6,
51.8, 56.8, 58.5, 59.0; Elemental analysis for C15H25NO4:
Calculated: C, 63.58; H, 8.89; N, 4.94; Found: C, 63.38; H,
8.98; N, 4.85; MS +FAB1): M11ˆ284.
3.1.8. *2S,3aS,7aR)-7a-Allyl-octahydroindole-1,2-dicar-
boxylic acid 1-tert-butyl ester 2-methyl ester *15). To a
solution of 14 +79.4 mg, 0.253 mmol) in dry CH2Cl2
+1.3 ml) allyltributyltin +235 ml, 0.759 mmol) was added
under argon atmosphere. This solution was added dropwise
to a solution of BF3´Et2O +128 ml, 1.012 mmol) in dry
CH2Cl2 +1.2 ml) at 2788C and stirred at this temperature
for 1 h, then warmed to 2208C. A phosphate buffer solution
+2.5 ml) was added and the aqueous phase was extracted
with CH2Cl2. The collected organic phases were dried
over Na2SO4, ®ltered and evaporated. The crude material
was puri®ed by ¯ash chromatography +hexane/EtOAc 9:1)
affording 79.8 mg +97%) of 15 +only 7aR-isomer) as a
22
3: [a]D ˆ294.4 +cˆ0.63, CHCl3); m.p. 54.0±54.58C
+n-pentane); 1H NMR +300 MHz, CDCl3) +mixture of
conformers) d 1.1±1.34 +m, 4H) 1.41, 1.47 +2s, 9H),
1.37±1.50+m, 2H), 1.70±1.89 +m, 3H), 2.22±2.32 +m,
1H), 2.63±3.10+m, 2H), 3.74 +s, 3H), 4.23, 4.29 +2bt,
1H); 13C NMR +75.4 MHz, CDCl3) +mixture of conformers)
d 24.8, 25.1, 26.1, 28.7, 28.8, 29.8, 31.6, 32.2, 34.6, 35.2,
46.1, 46.8, 52.3, 60.2, 60.5, 63.9, 64.2, 80.1, 154.1, 174.7;
IR +nujol) 1755, 1702, 1397, 1365, 1304, 1261, 1168, 1121,
1024, 902, 733 cm21; Elemental analysis for C15H25NO4:
Calculated: C, 63.58; H, 8.89; N, 4.94; Found: C, 63.70;
H, 8.90; N, 4.94.
22
1
colourless oil. [a]D ˆ126.9 +cˆ1.10, CHCl3); H NMR
+200 MHz, CDCl3): d 1.40+s, 9H), 1.20±2.55 +m, 11H),
2.65±3.0+m, 2H), 3.70+s, 3H), 3.85 +m, 1H), 5.10+m,
2H), 5.85 +m, 1H); 13C NMR +50.3 MHz, CDCl3) +mixture
of conformers): d 20.6, 23.5, 23.8, 25.7, 25.9, 26.0, 26.9,
28.4, 33.9, 34.9, 37.7, 39.3, 39.4, 40.3, 52.0, 58.7, 67.3,
67.6, 79.2, 79.8, 117.9, 118.1, 133.8, 134.2, 153.0, 173.4,
173.8; Elemental analysis for C18H29NO4: Calculated: C,
66.84; H, 9.04; N, 4.33; Found: C, 66.61; H, 8.95; N,
4.25; MS +FAB1): M11ˆ324.
3.1.6.
*2S,3aS,7aS)-Octahydroindole-1,2-dicarboxylic
acid 1-tert-butyl ester 2-methyl ester *2). To a solution
of 1 +638.8 mg, 2.37 mmol) in DMF +7.9 ml) KHCO3
+474.9 mg, 4.74 mmol) and CH3I +0.74 ml, 11.86 mmol)
were added. The solution was stirred at room temperature
overnight, then the solvent was evaporated. The crude
product was suspended in H2O +8 ml), extracted with
EtOAc and the collected organic phases were dried over
Na2SO4, ®ltered and evaporated. The crude material was
3.1.9. *2S,3aS,7aR)-7a-Allyl-octahydroindole-1,2-dicar-
boxylic acid 1-benzyl ester 2-tert-butyl ester *16). To a
solution of 15 +412.0mg, 1.27 mmol) in CH 2Cl2 +12.7 ml)
CF3COOH +4.9 ml, 63.5 mmol) was added dropwise and the
solution was stirred at room temperature for 1 h. The solvent
was evaporated under reduced pressure, the residue was
dissolved in a saturated NaHCO3 solution +13 ml), extracted
with CH2Cl2 and the collected organic phases were dried
over Na2SO4, ®ltered and evaporated. The crude material
was puri®ed by ¯ash chromatography +hexane/EtOAc 1:1)
affording 251.4 mg +89%) of N-deprotected octahydroindole
puri®ed by ¯ash chromatography +hexane/EtOAc 8:2)
yielding 666.5 mg +99%) of 2 as a colourless oil. [a]D
22
ˆ
1
232.7 +cˆ1.21, CHCl3); H NMR +200 MHz, CDCl3): d
1.45 +s, 9H), 0.8±2.1 +m, 10H), 2.10 +m, 1H), 3.55 +s,
3H), 3.60+m, 1H), 4.05 +m, 1H); 13C NMR +50.3 MHz,
CDCl3) +mixture of conformers): d 20.3, 23.4, 25.6, 27.2,
27.6, 28.0, 28.2, 31.4, 32.2, 36.2, 36.8, 51.6, 51.8, 56.8,
58.5, 59.0; Elemental analysis for C15H25NO4: Calculated:
C, 63.58; H, 8.89; N, 4.94; Found: C, 63.38; H, 8.98; N,
4.85; MS +FAB1): M11ˆ284.

L. Belvisi et al. / Tetrahedron 57 22001) 6463±6473
6471
22
derivative as a colourless oil. [a]D ˆ282.7 +cˆ1.10,
NMR +200 MHz, CDCl3) +mixture of conformers): d 1.10±
2.55 +m, 22H), 1.38 +s, 9H), 1.47 +s, 9H), 2.60±3.10+m, 4H),
3.90+m, 2H), 4.95±5.30+m, 8H), 5.90+m, 2H), 7.20±7.40
+m, 10H); 13C NMR +50.3 MHz, CDCl3) +mixture of confor-
mers): d 20.4, 20.6, 23.4, 23.6, 25.5, 25.6, 25.9, 26.9, 27.7,
33.8, 34.7, 37.3, 39.1, 40.5, 58.5, 59.3, 66.2, 66.7, 67.8,
68.4, 80.8, 80.9, 117.6, 117.9, 127.6, 127.7, 127.9, 128.2,
134.2, 134.6, 136.3, 137.1, 153.6, 172.9, 173.0; Elemental
analysis for C24H33NO4: Calculated: C, 72.15; H, 8.33; N,
3.51; Found: C, 72.29; H, 8.12; N, 3.62; MS +FAB1):
M11ˆ400.
1
CHCl3); H NMR +200 MHz, CDCl3): d 1.10±2.20 +m,
11H), 2.45 +ddd, 2H, Jˆ17 Hz, Jˆ8.8 Hz, Jˆ6.6 Hz),
3.25 +dd, 1H, Jˆ8 Hz, Jˆ4 Hz) 3.70+s, 3H), 3.90+s, 1H),
5.05 +m, 2H), 5.75 +m, 1H); 13C NMR +50.3 MHz, CDCl3):
d 21.4, 22.8, 26.4, 27.5, 37.8, 40.8, 45.3, 52.4, 57.8, 68.3,
118.2, 133.5, 177.1; Elemental analysis for C13H21NO2:
Calculated: C, 69.92; H, 9.48; N, 6.27; Found: C, 69.81;
H, 9.26; N, 6.08; MS +FAB1): M1ˆ223.
The previous compound +251.4 mg, 1.12 mmol) was
dissolved in EtOAc/H2O 1:1 +11.2 ml) and KHCO3
+224.3 mg, 2.24 mmol) and benzyl chloroformate +174 ml,
1.23 mmol) were added. The reaction was stirred vigorously
for 2 h, then the phases were separated and the aqueous
layer was washed with EtOAc. The combined organic
phases were dried over Na2SO4, ®ltered and evaporated.
The crude product was puri®ed by ¯ash column chroma-
tography +hexane/EtOAc 9:1) to provide the N-benzyloxy
derivative as a colourless oil +396.1 mg, 99% yield).
3.1.10. *2S,3aS,7aR)-7a-*2-Oxoethyl)-octahydroindole-
1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester
*17). To a solution of 16 +406.5 mg, 1.017 mmol) in
acetone/water 8:1 +10ml) OsCl 3 +29.6 mg) and
Me3NO´2H2O +226.0mg, 2.034 mmol) were added. The
solution was stirred at room temperature for 2 h, then
NaIO4 +543.8 mg, 2.54 mmol) was added and stirred for
2 h. The solvent was evaporated, the residue was dissolved
in water and extracted with EtOAc. The combined organic
phases were dried +Na2SO4), ®ltered and evaporated. The
crude material was puri®ed by ¯ash chromatography
+hexane/EtOAc 9:1) affording 17 +380.8 mg, 93%) as a
[a]D ˆ118.8 +cˆ1.21, CHCl3); 1H NMR +200 MHz,
22
CDCl3) +mixture of conformers): d 1.0±2.5 +m, 22H),
2.65±3.10+m, 4H), 3.50+s, 3H), 3.70+s, 3H), 3.90+m,
2H), 4.95±5.15 +m, 8H), 5.85 +m, 2H), 7.20±7.40 +m,
10H); 13C NMR +50.3 MHz, CDCl3) +mixture of confor-
mers): d 20.3, 20.4, 23.3, 23.4, 24.6, 25.5, 25.6, 25.9,
33.9, 34.8, 37.6, 38.8, 39.1, 40.7, 52.1, 52.3, 58.5, 59.2,
66.4, 66.7, 67.4, 68.0, 118.1, 127.6, 127.7, 127.8, 128.0,
128.3, 133.9, 134.1, 136.4, 136.9, 153.5, 153.6, 174.7;
Elemental analysis for C21H27NO4: Calculated: C, 70.56;
H, 7.61; N, 3.92; Found: C, 70.32; H, 7.80; N, 4.01; MS
+FAB1): M1357.
22
1
colourless oil. [a]D ˆ222.1 +cˆ0.96, CHCl3); H NMR
+200 MHz, CDCl3) +mixture of conformers): d 1.10±2.55
+m, 22H), 1.39 +s, 9H), 1.43 +s, 9H), 2.65±3.25 +m, 4H), 3.80
+m, 1H), 3.93 +m, 1H), 5.0±5.30 +m, 4H), 7.35 +m, 10H),
9.70+m, 1H), 9.88 +m, 1H); 13C NMR +50.3 MHz, CDCl3)
+mixture of conformers): d 20.4, 20.6, 23.5, 25.3, 25.4,
26.8, 27.5, 33.9, 34.9, 37.5, 48.3, 58.0, 58.8, 66.6,
67.0, 127.8, 128.0, 128.3, 199.2, 199.6; Elemental
analysis for C23H31NO5: Calculated: C, 68.80; H, 7.78;
N, 3.49; Found: C, 68.95; H, 7.77; N, 3.69; MS +FAB1):
M11ˆ402.
To
a solution of N-benzyloxy derivative +61.0mg,
0.170 mmol) in dioxane +1.7 ml) a 2N solution of LiOH
+0.42 ml, 0.85 mmol) was added and the solution was stirred
at 508C for 2 days. The solvent was evaporated, the residue
was dissolved in a 1 M solution of NaH2PO4 +1.7 ml) and
extracted with EtOAc. The organic phases were dried
+Na2SO4), ®ltered and evaporated affording the correspond-
ing acid +58.4 mg, 100%), as a yellowish solid, that was
submitted to the next reaction without further puri®cation.
1H NMR +200 MHz, CDCl3): d 1.05±2.5 +m, 11H), 2.65±
3.10+ddd, 2H, Jˆ15 Hz, Jˆ8.8 Hz, Jˆ6.6 Hz), 4.0+m, 1H)
5.0±5.20 +m, 4H), 5.85 +m, 1H), 7.20±7.40 +m, 5H), 11.5
+bs, 1H); 13C NMR +50.3 MHz, CDCl3) +mixture of confor-
mers): d 20.2, 20.4, 23.4, 23.6, 25.5, 25.9, 27.2, 34.0, 34.6,
37.2, 38.9, 39.1, 40.3, 58.9, 59.3, 66.9, 67.2, 68.3, 118.4,
118.6, 127.6, 127.7, 127.8, 128.0, 128.3, 128.4, 133.4,
133.7, 136.2, 136.5, 153.6, 154.6, 178.8, 180.3; MS
+FAB1): M11ˆ344.
3.1.11. *2S,3aS,7aR)-7a-*3-Benzyloxycarbonylamino-3-
methoxycarbonyl-allyl)-octahydroindole-1,2-dicarboxylic
acid 1-benzyl ester 2-tert-butyl ester *18). To a stirred
mixture of tBuOK +17.6 mg, 0.157 mmol) in 0.4 ml of dry
CH2Cl2 under nitrogen atmosphere, at 2788C, was added a
solution of Z-+a)-phosphonoglycine trimethyl ester
+52.2 mg, 0.157 mmol) in 0.4 ml of dry CH2Cl2. The solution
was stirred for 30min at this temperature and then a solution
of aldehyde 17 +42.0mg, 0.105 mmol) in dry CH 2Cl2
+0.5 ml) was added. The solution was stirred for 1 h at
2788C, then warmed to room temperature and stirred over-
night. A phosphate buffer +1.3 ml) was added and the
aqueous phase was extracted with CH2Cl2, dried over
Na2SO4 and the solvent evaporated under reduced pressure.
The crude material was puri®ed by ¯ash chromatography
+hexane/EtOAc 8:2), affording 54.1 mg +85%) of acrylic
1
The acid +380.5 mg, 1.11 mmol) was dissolved in dry
benzene +11 ml) and N,N-dimethylformamide di-tert-butyl
acetal +1.3 ml, 5.55 mmol) was added dropwise, the reaction
was re¯uxed for 1 h then Me2NCH+OtBu)2 +1.3 ml) was
added dropwise and the reaction was heated for 2 h, then
H2O +11 ml) was added. The phases were separated and the
aqueous layer was washed with EtOAc. The collected
organic phases were dried over Na2SO4, ®ltered and evapo-
rated. The crude residue was puri®ed by ¯ash chroma-
tography +hexane/EtOAc 9:1) yielding 409.9 mg +92%) of
ester 18 +1:1.5 E/Z ratio) as a colourless oil. H NMR
+300 MHz, CDCl3, 323 K) +Z/E mixture) +mixture of confor-
mers): d 1.32, 1.35, 1.43, 1.46 +4s, 18H), 1.1±2.6 +m, 22H),
3.0+m, 4H), 3.65, 3.70, 3.72, 3.75 +4s, 6H), 3.85±3.95 +m,
2H), 5.0±5.2 +m, 8H), 6.5 +bs, 0.8H), 6.6 +t, 1.2H, Jˆ7.8 Hz),
6.7 +bs, 1.2H), 6.8 +t, 0.8H, Jˆ7.8 Hz), 7.2±7.4 +m, 20H); 13C
NMR +50.3 MHz, CDCl3) +Z/E mixture) +mixture of confor-
mers): d 20.5, 20.6, 20.7, 23.5, 23.7, 25.5, 25.7, 26.0, 26.9,
27.0, 27.8, 28.3, 29.7, 30.0, 30.3, 33.4, 33.8, 34.0, 34.3, 34.5,
34.7, 34.9, 35.3, 37.4, 37.8, 38.9, 52.3, 58.6, 58.7, 59.3, 66.4,
66.7, 66.9, 67.2, 67.4, 68.0, 68.5, 68.9, 81.8, 125.5, 127.8,
22
1
16 as a colourless oil. [a]D ˆ14.0+ cˆ1.11, CHCl3); H

6472
L. Belvisi et al. / Tetrahedron 57 22001) 6463±6473
128.0, 128.2, 128.4, 128.5, 132.2, 133.4, 136.1, 136.9, 153.8,
154.2, 154.3, 165.1, 172.5; Elemental analysis for
C34H42N2O8: Calculated: C, 67.31; H, 6.98; N, 4.61; Found:
C, 67.55; H, 7.02; N, 4.49; MS +FAB1): M11ˆ607.
Acknowledgements
The authors thank CNR and MURST +COFIN 2000, ªSintesi
di Mimetici e Analoghi di Sostanze Naturali Biologicamente
Attiveº) for ®nancial support, and Dr. E. Milano and Dr. V.
Vinci for their valuable assistance.
3.1.12.
*2S,3aS,7aR)-7a-[3-*N-Benzyloxycarbonyl-N0-
tert-butoxycarbonylamino)-3-methoxycarbonyl-allyl]-
octahydroindole-1,2-dicarboxylic acid 1-benzyl ester
2-tert-butyl ester *19). A solution of 18 +45.2 mg,
0.074 mmol), +Boc)2O +32.5 mg, 0.149 mmol) and a cata-
lytic quantity of DMAP in 0.8 ml of dry THF, was stirred for
2 h under nitrogen. The solution was then quenched with
water +0.8 ml) and extracted with ethyl acetate. The organic
phase was dried over Na2SO4 and the solvent was evapo-
rated under reduced pressure. The crude material was puri-
®ed by ¯ash chromatography +hexane/EtOAc 8:2), yielding
46.0mg +88%) of 19 as a sticky solid.
References
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3.62, 3.68 +2s, 6H), 3.75±3.95 +m, 2H), 4.9±5.3 +m, 8H),
6.4 +m, 0.8H), 7.0 +m, 1.2H), 7.2±7.4 +m, 20H); 13C NMR
+50.3 MHz, CDCl3) +Z/E mixture) +mixture of conformers):
d 20.5, 23.6, 25.6, 26.9, 27.7, 33.4, 35.0, 52.1, 58.4, 59.4,
66.6, 67.0, 68.3, 76.3, 76.9, 77.6, 127.8, 128.4, 139.2, 143.0;
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3.1.13. *3S,6S,7aS,11aR) and *3R,6S,7aS,11aR)-3-tert-
[2,1-i]-
Butoxycarbonylamino-4-oxodecahydropyrido
indole-6-carboxylic acid tert-butyl ester *20, 21). A solu-
tion of 19 +95.2 mg, 0.134 mmol) and a catalytic quantity of
10% PdZC in 1.3 ml of MeOH was stirred under H2 over-
night. The catalyst was then ®ltered through celite and the
®ltration bed was washed with MeOH. The solvent was
evaporated under reduced pressure, the residue was
dissolved in toluene +13 ml) and re¯uxed for 48 h. The
solvent was removed and the two diastereoisomers formed
were separated by ¯ash chromatography +hexane/EtOAc
6:4), yielding 23.0mg of 20 and 23.4 mg of 21 +85%) +1:1
diastereoisomeric ratio) as sticky solids.
4. Belvisi, L.; Bernardi, A.; Manzoni, L.; Potenza, D.;
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22
1
20: [a]D ˆ122.6 +cˆ0.97, CHCl3); H NMR +300 MHz,
CDCl3) d 1.13±1.37 +3H), 1.44 and 1.52 +2s, 18H), 1.38±
1.55 +2H), 1.57±1.72 +4H), 1.88±2.00 +2H), 2.22±2.37
+2H), 2.47 +m, 1H), 2.56 +m, 1H), 3.95 +m, 1H), 4.32 +m,
1H), 5.68 +bs, 1H); 13C NMR +50.3 MHz, CDCl3): d 20.4,
23.4, 25.2, 25.8, 26.4, 27.7, 28.3, 30.2, 34.2, 40.4, 48.2,
57.6, 67.4, 79.2, 82.2, 172.8; Elemental analysis for
C22H36N2O5: Calculated: C, 64.68; H, 8.88; N, 6.85;
Found: C, 64.74; H, 8.78; N, 6.49; MS +FAB1):
M11ˆ409.
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 Â
J.; Catena, J.; Isabal, E.; Lopez-Canet, M.; Valls, N.
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 Â
Catena, J.; Terricabras, D.; Fernandez, J.-C.; Lopez-Canet,
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22
1
21: [a]D ˆ122.8 +cˆ1.05, CHCl3); H NMR +300 MHz,
CDCl3) d 1.05±1.35 +5H), 1.44 and 1.49 +2s, 18H), 1.52±
1.70+3H), 1.78 +m, 1H), 1.90±2.10+2H), 2.12±2.30+2H),
2.32±2.52 +2H), 4.10+m, 1H), 4.18 +m, 1H), 5.14 +bs, 1H);
13C NMR +50.3 MHz, CDCl3: d 20.1, 23.0, 25.2, 25.8, 27.1,
27.8, 28.2, 32.9, 34.6, 38.9, 50.9, 58.4, 67.7, 79.4, 82.2,
167.4, 174.1; Elemental analysis for C22H36N2O5: Calcu-
lated: C, 64.68; H, 8.88; N, 6.85; Found: C, 64.46; H,
8.96; N, 6.45; MS +FAB1): M11ˆ409.
Â
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