Synthesis of new bicyclic lactam peptidomimetics by ring-closing metathesis reactions

Article abstract of DOI:10.1016/S0040-4020(03)00684-7

An efficient and versatile synthetic method for the preparation of new fused bicyclic lactams 3a and 3b is described. The spirane cyclopentane nucleus was easily installed by diallylation of the pyroglutamate derivative 18 followed by ring-closing metathe

Full text of DOI:10.1016/S0040-4020(03)00684-7

Tetrahedron 59 (2003) 4501–4513
Synthesis of new bicyclic lactam peptidomimetics by ring-closing
metathesis reactions
a
a
b
c
Lino Colombo,a Marcello Di Giacomo, Valerio Vinci, Matteo Colombo, Leonardo Manzoni
,
*
and Carlo Scolasticob
a
`
Dipartimento di Chimica Farmaceutica, Universita di Pavia, Via Taramelli, 12, I-27100 Pavia, Italy
`
b
Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, Via Venezian, 21, I-20133 Milano, Italy
cCNR-ISTM Istituto di Scienze e Tecnologie Molecolari, Via Golgi 19, I-20133 Milano, Italy
Received 27 February 2003; revised 28 March 2003; accepted 29 April 2003
Abstract—An efficient and versatile synthetic method for the preparation of new fused bicyclic lactams 3a and 3b is described. The spirane
cyclopentane nucleus was easily installed by diallylation of the pyroglutamate derivative 18 followed by ring-closing metathesis (RCM). A
more practical and stereoselective method for the allylation of the a-methoxy carbamate 21, involving the use of InCl3 as a Lewis acid, was
developed. In the crucial coupling reaction of the diastereomeric mixture of cis- and trans-pirrolidine derivatives 5a and 5b with N-Cbz vinyl
phenylalanine only the cis isomer was found to react. An RCM reaction on the dipeptides 25a and 25b followed by catalytic hydrogenation,
gave the final epimeric bicyclic lactams 3a and 3b. The same synthetic sequence on the model compound 7, lacking the spiro cyclopentane
nucleus, is also reported. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Bradykinin (1) is a natural nonapeptide implicated in a great
variety of physiological disorders such as hyperalgesia,
inflammation and asthma.1 A rational design of potential
antagonists is made difficult by the lack of any knowledge
on a 3D structure of the ligand–receptor complex.2
Therefore, the synthesis of modified bradykinins could
provide useful information on the structural features
essential for receptor binding. One of the most active
Our continuing interest in the synthesis of conformationally
restricted peptidomimetics,6 based on bicyclic lactam
nonnatural bradykinin antagonist, derived from a modifi-
cation of the peptide chain, is Hoe-140 (2, Icatibant)3 in
derivatives, led us to consider whether the unnatural
which Pro,3 Phe,5 Pro,7 and Phe8 are replaced by Hyp, Thi,
dipeptide D-Tic-Oic could be mimicked by more con-
D-Tic, and Oic respectively. One additional unit of D-Arg is
strained structures like 3. The design of such molecules was
also linked to the peptide N terminus. It has been
based on the observation of a fairly good overlapping
hypothesized that the D-Tic7-Oic8 moiety is crucial for the
between some families of minimum energy conformations
bioactive conformation of the whole peptide as a site of a
of the D-Tic-Oic fragment and 5,7-fused bicyclic lactams
11. However, these dipeptide mimetics completely lack a
lipophilic portion that should mimic the fused cyclohexane
b-turn.4 Interest in bradykinin B2 receptor antagonists has
been further stimulated by the recent discovery that HOE-
140 exhibits mitogenic agonism in various tumour cell
ring of the octahydroindole nucleus. The presence of this
lines.5
structural unit may be important as a site of hydrophobic
interactions with the receptor. Thus we modified our
original targets by appending a spirocyclopentane moiety
to the C-4 position of the proline ring. Molecular mechanics
calculations7 showed a fairly good overlapping of some
families of minimum energy conformations of the N-acetyl
N0-methyl amide derivative of the D-Tic-Oic dipeptide and
the bicyclic peptidomimetic scaffold 3b (Fig. 1). It is
interesting to note that the bicyclic scaffold is able to adopt a
reverse-turn conformation. The RMS deviation in rigid
Keywords: ring-closing metathesis reaction; bicyclic lactam; Lewis acid.
Abbreviations: Hyp, trans-4-hydroxy-L-proline; Thi, 3-(2-thienyl)-L-
alanine; D-Tic, (R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; Oic,
PyBroPw,
(2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic
bromotripyrrolidinophosphoniumhexafluorophosphate.
*
acid;
Corresponding author. Tel.: þ39-382507387; fax: þ39-38242275;
e-mail: lino.colombo@mail.unipv.it
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00684-7

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L. Colombo et al. / Tetrahedron 59 (2003) 4501–4513
compound 7, lacking the spiro cyclopentane nucleus. On
the other hand, the simplified final products 11a and 11b
would be valuable per se as constrained mimics of the Phe-
Pro dipeptide.
2. Results and discussion
The starting N-Boc-5-allyl-L-proline methylester 7
(Scheme 2) was prepared according to a literature procedure
as an inseparable mixture of cis and trans isomers.9,10,13,14
Deprotection of the nitrogen protecting group allowed the
separation of the isomeric free amines 8a and 8b through
careful chromatographic purification. The subsequent
coupling with N-Cbz-vinyl phenylalanine 17 was attempted
using the amino acid in a racemic form. This choice was
dictated primarily by our need of preparing both epimers of
the final compound at the quaternary stereocenter. It seemed
more practical to rely on a chromatographic separation of
the diastereomeric pair of a suitable advanced intermediate
rather than to prepare both enantiomers of vinyl phenyl-
alanine, whose reported syntheses are lenghty and laborious,
particularly for gram scale preparations.15–20 Racemic 17
was prepared through a simplified modification of a
literature enantioselective method (Scheme 3).18 Benzyl-
ation of the lithium enolate derived from methyl 2-benz-
amido crotonate 1421 gave mainly the a-alkylated product
15, whose treatment with 6N HCl gave the fully deprotected
amino acid 16. Protection of the amine function as an N-Cbz
derivative was found to be not a trivial operation. High
yields could be obtained only through the use of non
aqueous conditions and di-benzyl dicarbonate as a
reagent.22 The key coupling reaction between the cis-
proline derivative 8a and N-Cbz vinyl phenylalanine 17
required extensive experimentation. Among the numerous
activating agents and reaction conditions tested,23 only
PyBroPw24 gave satisfactory results affording the dipeptides
9a and 9b in an acceptable 72% yield. The diastereomeric
pair of coupled products was obtained in an approximately
1:1 ratio and, fortunately, their DRf (0.37 vs. 0.28, n-Hex/
EtOAc 75:25) allowed an easy separation by flash
chromatography. When the same reaction was performed
on the trans-proline derivative 8b under identical experi-
mental conditions, no coupled product was obtained,
suggesting the occurrence of a strong kinetic resolution
effect. This was also proved by reacting an approximately
equimolar mixture of 8a and 8b with racemic N-Cbz vinyl
phenylalanine. Careful analysis of the reaction mixture
revealed the formation of the dipeptides deriving only from
the cis proline derivative 8a, while the trans isomer was
recovered unchanged in a yield close to 90%. Configura-
tional assignment of the quaternary stereocenter was
assured by correlation with a diastereomerically pure
sample of 9a, obtained by the same procedure but starting
from enantiomerically enriched (.95% e.e.) (R)-vinyl
phenylalanine, prepared on milligram scale according to
the method reported by Seebach.16
Figure 1.
superimposition between energy minimized conformations
˚
featuring a b-turn is 0.15 A for the dipeptide backbone
atoms.
Here we report on the synthesis of 3a and 3b by taking
advantage of ring closing metathesis (RCM) reactions8 for
constructing both the spirane cyclopentane moiety and the
5,7-fused bicyclic nucleus, as indicated in the retrosynthetic
sequence depicted in Scheme 1.
RCM reactions have been already applied to the synthesis of
bicyclic lactams like 3,9–12 but no examples are known in
which the vinyl component is linked to a quaternary
a-amino acid center. A major concern arises from the
coupling of the two amino acid units to give 4a,b. Extensive
literature search as SciFinder and Beilstein x-fire databases,
revealed the absence of any report on the peptide bond
formation between a 5-substituted proline and an
N-protected a,a-disubstituted amino acid. Therefore, we
decided to test the synthetic sequence on the model
The following RCM reaction was initially carried out
separately on each diastereomer. Good yields could be
obtained only by the use of the more thermally stable second
generation Grubbs catalyst 1325 or Hoveyda catalyst 12.26
The last one has the great advantage of being recoverable by
Scheme 1. Retrosynthetic analysis.

L. Colombo et al. / Tetrahedron 59 (2003) 4501–4513
4503
Scheme 2. (i) HCl/MeOH. (ii) PyBroPw, 17, DIEA, DMAP, CH2Cl2. (iii) 13, toluene, reflux. (iv) 10% Pd/C, H2, EtOH.
chromatography and hence reusable for further cycles. As
the DRf of the cyclized products 10a,b was higher than that
of their acyclic precursors (0.16, n-Hex/EtOAc 3:2, vs. 0.08,
n-Hex/EtOAc 3:1), we routinely performed the RCM step
on the diastereomeric mixture, postponing the chromato-
graphic separation of diastereoisomers to the cyclized
products. Saturation of the double bond and removal of
the N-Cbz prtotecting group was then effected in one
operation by standard catalytic hydrogenation, giving 11a
and 11b in 85 and 86% yield, respectively.
in pyroglutamates is highly regioselective and no epimer-
ization occurs at the stereocenter adjacent to the ester
function,27,28 the optical rotation value we measured for 6
was much lower than that reported for the corresponding
ethyl ester.27 In order to verify that no epimerization had
occurred under our modified conditions, the enantiomeric
excess of the advanced intermediate 20 was determined by
chiral HPLC and shown to be 99.6% (see Section 3 for
details). The spiro compound 20 was prepared by RCM of 6
followed by standard catalytic hydrogenation. Selective
reduction of the imide carbonyl with Et3LiBH29 was
followed, without purification, by treatment with trimethyl
orthoformate in methanol to give the N-Boc-N,O-acetal 21
in a diastereomeric ratio .95:5 (300 MHz NMR). The
configuration of the newly formed stereocenter was not
determined, since it should be converted into an sp2 center
in the subsequent allylation reaction that is known to
proceed via an intermediate acyliminium ion.30 Such
species are usually formed in situ by treatment of
hemiaminal derivatives with air sensitive Lewis acids at
low temperature. In order to make the allylation step more
practical, we briefly surveyed the use of Lewis acids which
could be effective for promoting the acyliminium ion
formation in less drastic conditions and possibly avoiding
the use of strictly anhydrous solvents. The screening was
Having established the feasibility of the proposed synthetic
sequence on the model compound, the stage was set for its
application to the spiro compounds 3a,b. Attachment of a
spirocyclopentane to the 4-position of methyl N-Boc
pyroglutamate was first attempted by bis-alkylation of the
imide enolate with 1,4-dihalo butanes and 1,4-dihalo-cis-2-
butenes, but only mediocre results were obtained. The
problem was circumvented by resorting to a double
allylation reaction of the pyroglutamate 1827 to give 6,
followed by a high yielding RCM reaction promoted by 24
(Scheme 4). By adjustment of the experimental conditions
we were able to increase the yields of the bis-allylation step
in comparison to those reported for an almost identical
substrate.27 Although it was reported that enolate formation
Scheme 3. (i) BnBr, LDA, THF/HMPA. (ii) 6N HCl, reflux. (iii) (Cbz)2O, Me4NOH, CH3CN.

4504
L. Colombo et al. / Tetrahedron 59 (2003) 4501–4513
Scheme 4. (i) Allyl Br, LiHMDS, THF/DMPU, 2788C. (ii) 24, DCM. (iii) 10% Pd/C, H2, EtOH. (iv) (a) LiEt3BH, THF, 2788C; (b) CH(OMe)3, PPTS, MeOH.
(v) Allyltrimethylsilane, InCl3, DCM. (vi) Bu4NF, THF. (vii) TFA/DCM.
restricted to indium and ytterbium salts and InCl3 was found
to give the best results in terms of yield and mildness of the
reaction conditions.31 Reaction of the crude a-methoxy
carbamate 21 with excess allyltrimethylsilane in the
presence of an equimolar amount of InCl3 in CH2Cl2 at
room temperature afforded the allylated adduct 22 in good
yields. Although all allylation reactions were run in
anhydrous CH2Cl2 (distilled over CaH2), the same trans-
formations also worked with reagent grade solvent in
comparable yields.
8a,b, whose relative configurations were known from
literature data (Table 1).32 A confirmation of this tentative
assignment was obtained from NOESY experiments on the
final compounds 3a and 3b (see below).
Beside the desired product, the InCl3 catalyzed allylation
reaction gave two side-products in 18 and 10% yield,
respectively. The former was immediately recognized as the
deprotected free amine 5 while the latter resulted from
intramolecular trapping of a b-silyl carbenium ion by the
N-Boc group, followed by the loss of 2-methylpropene.The
formation of such an oxazinone 23 from a-methoxycarba-
mates has already been reported in reactions catalyzed by
TiCl4.13 The stereochemical course of this reaction deserves
some comments. While the N-Boc protected allyl derivative
22 was formed with high stereoselectivity, the free amine 5
was produced as a 6:4 mixture of cis and trans isomers. This
result suggests that the deprotected allyl derivative 5 derives
from the trimethylsilyl oxazinone 23 through an elimination
reaction promoted by the attack of chloride ions on the
silicon atom of the cyclized intermediate (Scheme 5). This
hypothesis was corroborated by the following experiments.
Treatment of 22 with InCl3 under the same experimental
conditions as the allylation reaction did not afford any
deprotected product, excluding the hypothesis that 5a,b
could directly derive from 22 through the catalysis of the
Lewis acid. Moreover, the ratio between 5 and 22 is
considerably increased in favor of the desilylated product
when using longer reaction times. The intermediate silyl
oxazinone 23, that was formed as a mixture of only two out
of four possible diastereoisomers, by reaction with Bu4NF in
THF gave the N-deprotected allyl derivatives 5a,b with the
same diasteromeric ratio as the oxazinone 23. The use of
indium salts with non nucleophilic counterions such as
In(OTf)3 did not afford any deprotected product, supporting
the role of chloride ions as nucleophilic species that promote
the elimination of Me3SiCl from 23. However, the In(OTf)3
catalyzed allylation was of no synthetic value as the
allylated product was formed in very poor yield.
The reaction is highly diastereoselective, affording one
predominant diastereomer in a ratio .95:5 (400 MHz
NMR). 1D NOE and NOESY experiments were of no
avail for determining the relative configuration of the new
stereocenter. A tentative assignment was thought possible
by comparison of NMR data with those of the analogous cis
and trans compounds 7 lacking the spirocyclopentane
nucleus (Scheme 2). To this end, a method that could give
access to both diastereoisomers of 22 was needed. Taking
advantage of our previous experience on similar systems,6
we were able to obtain a 3:1 mixture of 22a and 22b by
reacting the crude reduction product from 20 with tributyl
allylstannane in the presence of t-butyl dimethylsilyl triflate
at 2788C, without prior conversion into the a-methoxy
carbamate derivative 21. Removal of the N-Boc protecting
group with TFA gave a chromatographically separable
mixture of 5a and 5b in the same ratio as the starting
material with the major isomer being identical to that
produced in the InCl3 promoted reaction. This was assigned
a cis-relative configuration by comparing chemical shifts of
relevant protons in 5a,b with the corresponding protons in
Table 1. Comparison of chemical shifts of H-2 and H-5 in compounds 5a,b
and 8a,b
dH-5a (ppm)
dH-2a (ppm)
8a
5a
8b
5b
3.15
2.87
3.25
3.09
3.78
3.79
3.81
3.83
Two possible explanations of the stereochemical divergence
in the formation of 22 with respect to 23 and 5 may be
advanced. The accepted mechanism33 of the allylation of
a
H-5 and H-2 are referred to the protons linked to carbons adjacent to the
allyl and carbomethoxy groups, respectively.

L. Colombo et al. / Tetrahedron 59 (2003) 4501–4513
4505
Scheme 5.
iminium ions and carbonyl compounds by allyltrimethyl-
silane involves the formation of an intermediate b-silyl
carbenium ion (intermediate B in Scheme 5) that undergoes
an elimination reaction by attack of a nucleophile on the
silicon center. In our particular case the carbenium ion B can
also follow a pathway leading to the iminium ion C and,
after elimination of 2-methyl-2-propene, to the final
oxazinone 23. If this mechanistic picture is true, the only
possible explanation of the stereoselective formation of 22
is that the elimination of Me3SiCl from the carbenium ion B
is much more faster on the cis than the trans isomer. At
present we cannot explain this kinetic resolution effect. We
can only speculate that the relative rate by which the
intermediate B can be converted in either C or 22a may be
dependent on the conformational preference of the Boc
carbonyl group. A trans conformational arrangement of the
proline peptide bond places the carbonyl oxygen far from
the carbocation, making more difficult the formation of
adduct C. It is, however, unclear how the conformational
properties of the intermediate B could be influenced by the
relative configuration of C-2 and C-5. An alternative,
simpler explanation is that the bicyclic intermediate C is
formed directly from the iminium ion A via a [4þ2]
cycloaddition with the double bond of the silane acting as a
dienophile. A concerted mechanism for the addition of
cyclic N-acyliminium ions and 2-silyloxy-1,3-dienes has
been already hypothesized.34
remove the residual carbamate protecting group. The
sequence from the spiro bicyclic pyroglutamate derivative
19 to the allylated free proline derivatives 5a,b was
routinely carried out without any purification in 59%
yield, that corresponds to a 88% average yield for each
step. The coupling reaction with racemic vinyl phenyl-
alanine proceeded using the same experimental conditions
as in the model study. Again, a remarkably higher reactivity
of the cis isomer allowed the use of the diastereomeric
mixture of 5a and 5b. The reaction of the separated trans
isomer did not proceed at a detectable rate under the usual
conditions allowing an almost complete recovery of the
unaffected starting material. The ensuing RCM reaction, as
in the case of the model compound, was performed on the
mixture of the two diastereomers, since the DRf of the
cyclized products was higher than that of the acyclic
dipeptides. The assignment of the configuration of the
quaternary stereocenter was assigned as before by corre-
lation with a diastereomerically pure compound prepared
from enantio-enriched N-Cbz vinyl phenyl alanine (.95%
e.e.).16
Repetition of the last two steps, under the same conditions
as the model study, gave without, any difficulties, the final
compounds 3a and 3b with the yields indicated in Scheme 6.
Molecular mechanics calculations performed on the R
isomer 3b showed that in some minimum energy confor-
mations the distance between the benzylic protons and the
hydrogen atom linked to the bicyclic lactam fusion carbon
was short enough to observe an NOE correlation. As a
matter of fact, the NOESY spectrum of 3b showed a small
In practice, we treated the crude allylation reaction mixture
with Bu4NF and, after aqueous workup without purification,
submitted the crude product to reaction with TFA in order to

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L. Colombo et al. / Tetrahedron 59 (2003) 4501–4513
MeCN from P2O5 under nitrogen. TLC was performed on
Kieselgel 60 F254 (Merck) glass Plate with detection by UV
light, iodine, or a solution of 4,40- methylenebys-N,N-
dimethylaniline, ninidrine, KI in an aqueous ethanolic
solution of AcOH. Flash chromatography was performed on
Merck Kieselgel 60 (230–400 mesh). Melting points were
determined on a Kofler apparatus and are uncorrected.
Optical rotations were measured at 208C with a Perkin–
Elmer 343 polarimeter. The 1H (300 and 400 MHz) and 13
C
NMR (75 and 100 MHz) spectra were recorded with Bruker
Avance 300 and 400 instruments, respectively. In the peak
listing of 13C spectra abbreviations s and t refer to zero and
two protons attached to the carbons, as determined by DEPT
experiments. Infrared spectra were recorded on a Perkin–
Elmer FTIR 1600 series spectrometer. Mass spectra were
recorded on a Finnigan LCQ-DECA mass spectrometer.
Elemental analyses were performed on a Carlo Erba
Elemental Analyzer Mod. 1106.
3.1.1. (5R and 5S,2S)-5-Allyl-pyrrolidine-1,2-dicar-
boxylic acid 1-tert-butyl ester 2-methyl ester (7a and
7b). A 1.0 M solution of lithium triethylborohydride in THF
(9.86 mL, 9.86 mmol) was added to a solution of (S)-N-Boc
pyroglutamic acid methyl ester (18) (2.0 g, 8.22 mmol) in
THF (50 mL) at 2788C under a nitrogen atmosphere. After
30 min the reaction mixture was quenched with saturated
aqueous NaHCO3 (15 mL) and warmed to 08C. Thirty
percent H2O2 (1.5 mL) was added, and the mixture was
stirred at 08C. After 20 min the organic solvent was
removed in vacuo, and the aqueous phase was extracted
with CH2Cl2 (3£30 mL). The combined organic layers were
dried, filtered and evaporated to dryness. The crude reaction
mixture was used without purification and dissolved in
CH2Cl2 (80 mL) under nitrogen. After the addition of
allyltributyltin (3.06 mL, 9.86 mmol) the solution was
cooled to 2788C and t-butyldimethylsilyl trifluoromethane-
sulphonate (2.26 mL, 9.86 mmol) was added. After 20 min
the reaction was quenched with saturated aqueous NaHCO3
(15 mL), extracted with CH2Cl2 (3£30 mL), dried and
evaporated. Purification by flash chromatography eluting
first with C6H14 and then C6H14/AcOEt 85:15 gave 1.66 g
(75%) of an inseparable 65:35 mixture of 7a and 7b as a
Scheme 6. (i) PyBroPw, 17, DIEA, DMAP, CH2Cl2. (ii) 12, DCE. (iii) 10%
Pd/C, H2, MeOH.
but unequivocal cross peak correlating these protons. No
such correlation was evidenced by the NOESY spectrum of
the S isomer. This is a definite proof of the cis relationship
between the two hydrogen atoms flanking the proline
nitrogen, thus confirming the tentative stereochemical
assignment discussed above.
1
colorless oil. TLC Rf 0.35 (C6H14/AcOEt 85:15). H NMR
(CDCl3, 400 MHz, mixture of diatereoisomers and con-
formers) d: 1.40 and 1.47 (2s, 9H: 1.9:1), 1.56–1.83 (m,
1H), 1.83–2.29 (m, 4H), 2.38–2.78 (bm, 1H), 3.71 and 3.73
(s, 3H: 1:1.9), 3.80–4.12 (3m, 1H), 4.16–4.36 (m, 1H),
4.99–5.12 (m, 2H), 5.67–5.87 (m, 1H). 13C NMR (CDCl3,
100 MHz, mixture of diatereoisomers and conformers) d:
28.4, 28.6, 28.7, 29.1 (t), 29.9 (t), 38.5 (t), 38.6 (t), 39.3 (t),
39.5 (t), 52.2, 52.4, 57.8, 57.9, 58.3, 58.4, 59.9, 60.1, 60.2,
60.5, 80.2 (s), 80.3 (s), 117.2 (t), 117.6 (t), 117.7 (t), 135.4,
135.5, 135.7, 153.9 (s), 154.0 (s), 154.6 (s), 154.7 (s), 173.7
(s), 174.0 (2 peaks, s), 174.2 (s). IR (neat) 1752, 1701, 1655,
1640, 1391, 1172 cm21. MS (ESI) m/z 270.2 [MþH]þ,
292.2 [MþNa]þ. Anal. calcd for C14H23NO4: C, 62.43; H,
8.61; N, 5.20. Found: C, 62.31; H, 8.54; N, 5.12.
In conclusion we have developed an efficient approach
toward new bicyclic lactams. The novel elements intro-
duced in this synthetic sequence are a practical and
stereoselective allylation reaction on an acyliminium ion
catalyzed by InCl3 and a peptide bond formation between
5-substituted proline derivatives and a N-protected a,a-
disubstituted amino acid. The conformationally constrained
peptidomimetics we have so prepared have been inserted in
place of the D-Tic-Oic fragment in HOE-140 analogues.
The solid phase synthesis of these nonapeptides and their
biological activity as bradykinin antagonists will be
reported elsewhere.
3.1.2. (5R and 5S,2S)-5-Allyl-pyrrolidine-2-carboxylic
acid methyl ester (8a and 8b). A solution of the 65:35
mixture of 7a and 7b (1.540 g, 5.72 mmol) in saturated HCl
methanol was stirred at 08C for 10 min. The reaction
mixture was evaporated and the solid residue was used
3. Experimental
3.1. General
THF was distilled from sodium/benzophenone ketyl and

L. Colombo et al. / Tetrahedron 59 (2003) 4501–4513
4507
without purification for the next reaction. For sake of
characterization, a sample of the crude hydrochloride salt
(205 mg) was dissolved in 2 mL of water, treated with solid
Na2CO3 until pH 8–9, and extracted with AcOEt (5£5 mL).
The combined organic layers were dried and evaporated to
give an oily residue that was purified by flash chromato-
graphy (Et2O/MeOH 97:3) to give 8a (0.352 g, 36.4%) and
8b (0.170 g, 17.6%). (spectroscopic data of 8a and 8b were
in agreement with those provided to us by Professor
K. Moeller).32
75:25). [a]D¼263.5 (c 1.1, MeOH). IR (nujol) 3311, 1751,
1735, 1654, 1637 cm21 1H NMR (DMSO-d6, 808C,
.
400 MHz) d: 1.54 (bs, 1H), 1.86 (bs, 3H), 2.08–2.26 (bm,
1H), 2.76 (bs, 1H), 3.02 (s, 1H), 3.07 (d, 1H, J¼13.3 Hz),
3.60 (s, 3H), 3.56–3.69 (m, 1H), 4.15 (bs, 1H), 4.57 (bs,
1H), 4.87–5.27 (m, 5H), 5.22 (d, 1H, J¼11.0 Hz), 5.70–
5.91 (m, 1H), 5.93 (dd, 1H, J¼10.9, 17.7 Hz), 6.92–7.01
(m, 2H), 7.11–7.21 (m, 4H), 7.30–7.44 (m, 4H). 13C NMR
(DMSO-d6, 808C, 100 MHz) d: 28.6 (t), 38.6 (bt), 42.6 (bt),
51.8, 59.1 (b), 60.8 (b), 64.8 (s), 66.1 (t), 115.4 (bt), 116.5
(bt), 126.4, 127.9, 128.2, 128.4, 128.6, 131.2, 136.2, 137.1
(s), 137.3 (s), 138.4, 154.6 (s), 170.2 (s), 172.7 (s) (one
broad signal is obscured by the solvent). MS (ESI) m/z 477.2
[MþH]þ, 499.3 [MþNa]þ. Anal. calcd for C28H32N2O5: C,
70.57; H, 6.77; N, 5.88. Found: C, 70.41; H, 6.58; N, 5.61.
Compound 8a. Pale yellow oil. TLC Rf 0.38 (Et2O/MeOH
97:3). [a]D¼223.4 (c 0.7, CHCl3). IR (film) 3347, 3074,
2953, 1737, 1639, 1436 cm21. 1H NMR (CDCl3, 400 MHz)
d: 1.29–1.42 (m, 1H), 1.85–1.98 (m, 2H); 2.05–2.17 (m,
1H), 2.19–2.37 (m, 3H, 2H after exchange with D2O), 3.15
(m, 1H), 3.74 (s, 3H), 3.78 (dd, 1H, J¼5.8, 8.8 Hz), 5.06
(broad d, 1H, J¼10.1 Hz), 5.12 (dd, 1H, J¼17.1, 1.5 Hz),
5.83 (ten lines system, J¼10.1, 17.1, 7.0 Hz). 13C NMR
(CDCl3, 100 MHz) d: 29.9 (t), 30.8 (t), 39.9 (t), 52.0, 59.0,
59.6, 116.7 (t), 135.4, 175.3 (s). MS (ESI) m/z 170.2
[MþH]þ, 192.2 [MþNa]þ. Anal. calcd for C9H15NO2: C,
63.88; H, 8.93; N, 8.28. Found: C, 63.71; H, 8.97; N, 8.12.
Compound 9b. Glassy solid. TLC Rf 0.29 (C6H14/AcOEt
75:25). [a]D¼þ19.4 (c 0.9, MeOH). IR (nujol) 3369, 1728,
1
1636 cm21. H NMR (DMSO-d6, 808C, 400 MHz) d: 1.63
(bs, 2H), 1.79–1.95 (m, 1H), 1.95–2.22 (m, 2H), 2.39–2.62
(bs, 1H), 3.02 (bs, 1H), 3.11 (d, 1H, J¼13.5 Hz), 3.52 (bd,
1H), 3.62 (s, 3H), 4.02–4.13 (bm, 1H), 4.62 (bs, 1H), 4.96–
5.13 (m, 5H), 5.16 (d, 1H, J¼11.0 Hz), 5.69–5.85 (m, 1H),
5.93 (dd, 1H, J¼11.0, 17.6 Hz), 6.96–7.04 (m, 2H), 7.14–
7.24 (m, 3H), 7.28–7.43 (m, 5H).). 13C NMR (DMSO-d6,
808C, 100 MHz) d: 28.2 (t), 38.1 (bt), 42.5 (bt), 51.8, 58.9
(b), 60.4 (b), 64.7 (bs), 66.1 (t), 115.0 (t), 117.0 (bt), 126.5,
128.0, 128.2, 128.4, 128.6, 131.2, 136.0, 136.9 (s), 137.3 (s),
138.4, 154.7 (s), 169.8 (s), 172.8 (s) (one broad signal is
obscured by the solvent). MS (ESI) m/z 477.2 [MþH]þ,
499.3 [MþNa]þ. Anal. calcd for C28H32N2O5: C, 70.57; H,
6.77; N, 5.88. Found: C, 70.41; H, 6.58; N, 5.71.
Compound 8b. TLC Rf 0.47 (Et2O/MeOH 97:3).
[a]D¼238.8 (c 0.7, CHCl3). IR (film) 3349, 3074, 2956,
1
1736, 1641, 1437 cm21. H NMR (CDCl3, 400 MHz) d:
1.31–1.44 (m, 1H), 1.75–1.91 (m, 2H), 2.05–2.23 (m, 3H),
2.35 (bs, 1H, exchanges with D2O), 3.25 (m, 1H), 3.67 (s,
3H), 3.81 (dd, 1H, J¼5.8, 8.6 Hz), 4.99 (d, 1H, J¼10.2 Hz),
5.03 (dd, 1H, J¼17.1, 1.5 Hz), 5.76 (ten lines system,
J¼10.1, 17.2, 7.0 Hz). 13C NMR (CDCl3, 100 MHz) d: 29.3
(t), 30.7 (t), 40.6 (t), 51.9, 57.6, 58.8, 116.4 (t), 135.8, 176.0
(s). MS (ESI) m/z 170.2 [MþH]þ, 192.2 [MþNa]þ. Anal.
calcd for C9H15NO2: C, 63.88; H, 8.93; N, 8.28. Found: C,
63.71; H, 9.02; N, 8.20.
3.1.4. (6R and 6S)-6-Benzyl-6-benzyloxycarbonylamino-
5-oxo-(2R)-2,3,5,6,9,9a-hexahydro-1H-pyrrolo[1,2-
a]azepine-(3S)-3-carboxylic acid methyl ester (10a and
10b). A solution of 9a (165 mg, 0.35 mmol) and catalyst 13
(14 mg, 0.02 mmol) in toluene was refluxed under nitrogen
for 2 h. Lead (IV) acetate (18 mg, 0.04 mmol) was added
and the stirring continued overnight.35 The solvent was
evaporated and the crude mixture was chromatographed
(C6H14/AcOEt 6:4) to give pure 10a (132 mg, 85%). The
same procedure, applied to 9b (172 mg, 0.36 mmol) gave,
after flash chromatography (C6H14/AcOEt 75:25), 131 mg
(81%) of 10b and 12 mg of starting material 9b.
3.1.3. (5R)-5-Allyl-1-[(2R and 2S)-2-benzyl-2-benzyloxy-
carbonylamino-but-3-enoyl]-pyrrolidine-(2S)-2-car-
boxylic acid methyl ester (9a and 9b). To a CH2Cl2
solution (16 mL) of 17 (1.152 g, 3.54 mmol) was added
PyBroPw (1.980 g, 4.25 mmol) and DIEA (1.85 mL,
10.62 mmol), and the mixture was stirred at room
temperature for 1 h under nitrogen. The crude 1:1.9 mixture
of the hydrochloride salt of 8a and 8b (728 mg, 3.54 mmol)
obtained from the previous reaction was added, followed by
the addition of DIEA (1.85 mL, 10.62 mmol) and DMAP
(216 mg, 1.77 mmol). The resulting mixture was stirred at
room temperature for 4 days. (The reaction time could be
decreased by refluxing for 12 h, without substantially
affecting the yield.) The solvent was reduced to a small
volume by evaporation and the residue, after dilution with
AcOEt (30 mL), was washed with an aqueous 5% solution
of KHSO4, saturated NaHCO3 and water. Evaporation of the
solvent gave an oily residue that was purified by flash
chromatography (C6H14/AcOEt 75:25) to give 790 mg of an
approximately 1:1 mixture of 9a and 9b (72% with respect
to the amount of 8a). For sake of characterization a sample
of the above mixture (204 mg) was submitted to further
flash chromatography (C6H14/AcOEt 73:27) giving pure 9a
(96 mg) and 9b (101 mg).
Compound 10a. White amorphous solid, mp 37–388C. TLC
Rf 0.30 (C6H14/AcOEt 6:4). [a]D¼2144.9 (c 0.8, CDCl3).
IR (nujol) 3323, 1717, 1653 cm21 1H NMR (CDCl3,
.
400 MHz) d: 1.63–1.78 (bm, 1H), 1.94 (bs, 2H), 2.12 (bs,
1H), 2.22–2.32 (m, 1H), 2.39–2.51 (m, 1H), 3.13 (d, 1H,
J¼14.0 Hz), 3.61 (d, 1H, J¼14.0 Hz), 3.77 (s, 3H), 4.51–
4.72 (bm, 2H), 4.94 (bs, 1H), 5.02–5.50 (bm, 2H), 5.68
(apparent d, 1H, J¼11.9 Hz), 5.75–5.84 (m, 1H), 7.06–7.13
(bm, 2H), 7.20–7.28 (bm, 3H), 7.32–7.46 (m, 5H). 13C
NMR (CDCl3, 100 MHz) d: 27.4, 32.8, 35.8, 40.9, 52.5,
54.5, 60.1, 61.8, 67.1, 127.0, 127.1, 128.5, 128.8, 129.0 (2
peaks), 132.0, 133.5, 136.8, 154.1, 170.0, 173.8. MS (ESI)
m/z 449.3 [MþH]þ, 471.2 [MþNa]þ. Anal. calcd for
C26H28N2O5: C, 69.63; H, 6.29; N, 6.25. Found: C, 69.81;
H, 6.42; N, 6.44.
Compound 9a. Foamy solid. TLC Rf 0.37 (C6H14/AcOEt
Compound 10b. White prisms, mp 119–1208C (from

4508
L. Colombo et al. / Tetrahedron 59 (2003) 4501–4513
EtOH). TLC Rf 0.46 (C6H14/AcOEt 6:4). [a]D¼2120.3 (c
1.6 M in n-hexane). The resulting deep-red solution was
stirred for 5 min at 2788C. Benzyl bromide (2.90 mL,
24.5 mmol) in THF (11 mL) at 2788C was then added via
cannula. After 40 min the reaction mixture was poured in
ether (100 mL) and saturated aqueous NH4Cl (150 mL).
After further extraction of the aqueous phase with ether
(3£50 mL), the combined organic layers were dried and
evaporated. Flash chromatography (C6H14/AcOEt 82:18)
provided 15 (2.558 g, 73%) as a white solid. Mp 104–
1068C. TLC Rf 0.35 (C6H14/AcOEt 82:18). IR (nujol) 3285,
1
0.7, CDCl3). IR (nujol) 3373, 1747, 1715, 1643 cm21. H
NMR (CDCl3, 400 MHz) d: 1.80–1.93 (m, 1H), 2.02–2.19
(m, 2H), 2.23–2.40 (m, 2H), 2.54–2.66 (m, 1H), 3.24 (d,
1H, J¼13.8 Hz), 3.71 (s, 3H), 3.85 (d, 1H, J¼13.8 Hz), 4.27
(bm, 1H), 4.49 (dd, 1H, J¼2.9, 8.2 Hz), 5.09 (d, 1H,
J¼12.5 Hz), 5.21 (d, 1H, J¼12.5 Hz), 5.75 (ddd, 1H, J¼2.3,
6.9, 12.4 Hz), 6.33 (d, 1H, J¼12.4 Hz), 6.57 (s, 1H), 6.88–
6.94 (m, 2H), 7.14–7.24 (m, 3H), 7.30–7.42 (m, 5H). 13C
NMR (CDCl3, 100 MHz) d: 27.7 (t), 32.7 (t), 34.9 (t), 42.3
(t), 52.6, 56.6, 62.7, 64.8 (s), 66.3 (t), 126.7, 127.5, 128.3,
128.6, 128.8, 129.0, 130.1, 135.8 (s), 137.4 (s), 154.9 (s),
169.9 (s), 172.9 (s). MS (ESI) m/z 449.3 [MþH]þ, 471.2 [M
þ Na]þ. Anal. calcd for C26H28N2O5: C, 69.63; H, 6.29; N,
6.25. Found: C, 69.68; H, 6.34; N, 6.21.
1
1745, 1647, 1541 cm21. H NMR (CDCl3, 400 MHz) d:
3.46 (d, 1H, J¼13.5 Hz), 3.85 (s, 3H), 3.94 (d, 1H,
J¼13.5 Hz), 5.34 (d, 1H, J¼17.3 Hz), 5.37 (d, 1H,
J¼10.6 Hz), 6.22 (dd, 1H, J¼10.6, 17.3 Hz), 7.03 (bs,
1H), 7.08–7.14 (m, 2H), 7.21–7.27 (m, 3H), 7.40–7.54 (m,
3H), 7.70–7.76 (m, 2H). 13C NMR (CDCl3, 100 MHz) d:
40.4 (t), 53.5, 66.2 (s), 116.7 (t), 127.4, 127.5, 128.7, 129.1,
130.4, 132.1, 135.1 (s), 136.1 (s), 136.7, 166.7 (s), 172.8 (s).
MS (ESI) m/z 310.2 [MþH]þ, 332.2 [MþNa]þ. Anal. calcd
for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.68;
H, 6.25; N, 4.61.
3.1.5. (6R and 6S)-6-Benzyl-6-amino-5-oxo-(2R)-octa-
hydro-1H-pyrrolo[1,2-a]azepine-(3S)-3-carboxylic acid
methyl ester (11a and 11b). A solution of 10a (60 mg,
0.13 mmol) in EtOH (2 mL) was added of Pd, 10% wt on
activated carbon, (6 mg) and stirred under a positive
pressure of hydrogen for 24 h. After filtration on celitew
and careful washing with the same solvent the colorless
solution was evaporated. The crude product (40 mg) was
purified by flash chromatography (AcOEt/Et3N 95:5) to
give pure 11a (36 mg, 86%) as an oil. The same procedure,
applied to 10b (58 mg, 0.13 mmol) gave, after flash
chromatography (C6H14/AcOEt 75:25), 35 mg (85%) of
11b as a white solid.
3.1.7. 2-Amino-2-benzyl-but-3-enoic acid hydrochloride
salt (16). A suspension of 15 (2.258 g, 7.30 mmol) in 6N
HCl (60 mL) was refluxed under vigorous stirring for 4 h.
The reaction mixture was cooled to room temperature and
extracted with CH2Cl2 (3£30 mL). The aqueous phase was
evaporated and the white solid residue dried under vacuum
in a dessicator in the presence of abundant P2O5 until
constant weight (1.546 g, 93%). The spectral data were in
accordance with those reported for enantiomerically
enriched (R)-16.16
Compound 11a. TLC Rf 0.42 (EtOAc/Et3N 95:5).
[a]D¼273.8 (c 0.3, CDCl3). IR (nujol) 3364, 1740,
1629 cm21 1H NMR (CDCl3, 400 MHz) d: 1.72–2.24
.
(m, 8H), 2.33–2.49 (bs, 1H), 2.60–2.79 (bs, 1H), 3.25 (d,
1H, J¼13.8 Hz), 3.25 (bs, 1H, exchanges with D2O), 3.38
(d, 1H, J¼13.8 Hz), 3.53–3.67 (bs, 1H, exchanges with
D2O), 3.77 (s, 3H), 4.01 (bs, 1H), 4.61 (d, 1H, J¼7.8 Hz),
7.17–7.52 (m, 5H). 13C NMR (CDCl3, 100 MHz) d: 20.4
(t), 27.5 (t), 30.3 (t), 31.5 (t), 33.5 (t), 42.3 (t), 52.8, 59.0,
62.5, 62,6 (s), 128.0, 128.7, 132.0, 133.5 (s), 169.5 (s), 173.2
(s). MS (ESI) m/z 449.3 [MþH]þ, 471.2 [MþNa]þ. Anal.
calcd for C18H24N2O3: C, 68.33; H, 7.65; N, 8.85. Found: C,
68.54; H, 7.38; N, 8.69.
3.1.8. 2-Benzyl-2-benzyloxycarbonylamino-but-3-enoic
acid (17). To a stirred solution of 16 (1.363 g, 5.99 mmol)
in anhydrous CH3CN (60 mL) under nitrogen was added
tetramethylammonium hydroxide pentahydrate (2.168 g,
12.0 mmol). The solution slowly becomes gelatinous and
after 30 min dibenzyl dicarbonate (2.576 g, 9.0 mmol) was
added, causing the conversion of the gel into an almost clear
solution. After 4 h a further portion of dibenzyldicarbonate
was added and the stirring continued for 16 h. The solvent
was evaporated and the residue, dissolved in aqueous
sodium carbonate, washed with ether (2£30 mL) and slowly
acidified to pH 1–2. The aqueous phase was then extracted
with EtOAc (3£30 mL) and the combined organics dried
and evaporated to give 1.748 g of 17 (90%), sufficiently
pure to be used in the following coupling reaction. For the
sake of characterization a sample of crude 17 (158 mg) was
purified by flash chromatography (EtOAc/MeOH 99:1) to
give 146 mg of pure compound as a colorless oil. TLC Rf
0.42 (EtOAc/MeOH 99:1). IR (nujol) 3400, 3033, 1709,
Compound 11b. White needles, mp 96–978C (from C6H14).
TLC Rf 0.37 (EtOAc/Et3N 95:5). [a]D¼290.5 (c 0.9,
CDCl3). IR (nujol) 3363, 1744, 1634 cm21 1H NMR
.
(CDCl3, 400 MHz) d: 1.56–2.32 (m, 10H), 3.04 (d, 1H,
J¼13.4 Hz), 3.31 (bd, 1H, J¼13.4 Hz), 3.76 (s, 3H), 3.88
(bm, 1H), 4.49 (d, 1H, J¼7.1 Hz), 4.83 (bs, 2H, exchange
with D2O), 7.01–7.40 (m, 5H). 13C NMR (CDCl3,
100 MHz) d: 23.1 (bt), 27.5 (t), 33.7 (t), 34.8 (bt), 40.7
(bt), 52.9, 59.3 (b), 62.7, 63.5 (s), 127.6, 129.0, 130.3,
135.2 (s), 172.9 (s), 173.2 (s).). MS (ESI) m/z 449.3
[MþH]þ, 471.2 [MþNa]þ. Anal. calcd for C18H24N2O3:
C, 68.33; H, 7.65; N, 8.85. Found: C, 68.41; H, 7.59; N,
8.93.
1
1495, 1446 cm21. H NMR (CDCl3, 400 MHz) d: 3.39 (d,
1H, J¼13.4 Hz), 3.60 (d, 1H, J¼13.4 Hz), 5.11 (d, 1H,
J¼12.2 Hz), 5.21 (d, 1H, J¼12.2 Hz), 5.34 (d, 1H, J¼
17.3 Hz), 5.37 (d, 1H, J¼10.6 Hz), 5.59 (bs, 1H), 5.67–6.37
(bs, 1H), 6.11 (dd, 1H, J¼10.6, 17.3 Hz), 7.04–7.11 (m,
2H), 7.16–7.26 (m, 3H), 7.35–7.45 (m, 5H). 13C NMR
(CDCl3, 100 MHz) d: 40.8 (t), 65.4 (s), 67.3 (t), 116.8 (t),
127.5, 128.2, 128.7 (2 peaks), 129.0, 130.5, 135.6 (s), 136.6,
136.7 (s), 155.1 (s), 176.3 (s). MS (ESI) m/z 326.2 [MþH]þ,
348.3 [MþNa]þ. Anal. calcd for C19H19NO4: C, 70.14; H,
5.89; N, 4.30. Found: C, 70.27; H, 5.92; N, 4.53.
3.1.6. 2-Benzoylamino-2-benzyl-but-3-enoic acid methyl
ester (15). To a 0.2 M solution of LDA (12 mmol) in a 1:2
mixture of THF/HMPA (60 mL) maintained under nitrogen
at 2788C was added 14 (2.475 g, 11.3 mmol) in THF
(50 ml) via cannula, followed by butyllithium (14 mL,

L. Colombo et al. / Tetrahedron 59 (2003) 4501–4513
4509
3.1.9. (2S)-4,4-Diallyl-5-oxo-pyrrolidine-1,2-dicar-
boxylic acid 1-tert-butyl ester 2-methyl ester (6). To a
solution of 18 (2.5 g, 10.3 mmol) in dry THF (100 mL)
stirred at 2788C under nitrogen was added a 1 M solution
of lithium hexamethyldisilazide in THF (22.6 mL,
22.6 mmol), followed, after 15 min, by the addition of dry
DMPU (6.2 mL, 51.5 mmol) and freshly distilled alllyl
bromide (1.78 mL, 20.6 mmol). After stirring for 30 min,
the temperature was slowly raised to 2308C and the mixture
stirred at this temperature for 90 min, after which time the
pale yellow solution was quenched with saturated NH4Cl
and extracted with CH2Cl2 (3£60 mL). The combined
organic phases were dried and evaporated. The product was
purified by flash chromatography (C6H14/AcOEt 85:15)
giving the diallylated product (6) (1.366 g, 41%) as a
colorless oil and a mixture of cis- and trans- monoallylated
products (1.263 g, 43%) whose spectral data were in full
agreement with those reported in the literature.6,36 This
diastereomeric mixture was submitted to a further allylation
using the same procedure as above (1.1 equiv. of base and
1.2 equiv. of allyl bromide, quenching at 2608C) to give,
after chromatography, 1.010 g of 6 (70%), corresponding to
a global yield of 71%. TLC Rf 0.61 (C6H14/AcOEt 7:3).
[a]D¼218.7 (c 1.0, CHCl3). The lit. value of the
corresponding ethyl ester is: [a]D¼2169.7 (c 0.35,
hydrogenated under pressure (3 atm of H2) overnight in the
presence of Pd, 10% wt on activated carbon (200 mg). After
filtration on celitew and careful washing with the same
solvent the colorless solution was evaporated to give
2.092 g (98%) of 20 as a white solid, sufficiently pure to
be processed in the next reaction. Mp 43–448C (white
needles from C6H14). TLC Rf 0.46 (C6H14/AcOEt 7:3).
[a]D¼216.8 (c 1.0, CDCl3). IR (nujol) 1779, 1732, 1355,
1304 cm21 1H NMR (CDCl3, 300 MHz) d: 1.44–174
.
(mþs, 13H), 1.75–1.92 (m, 2H), 1.99 (dd, 1H, J¼4.5,
13.2 Hz), 1.99–2.13 (m, 2H), 2.25 (dd, 1H, J¼9.2,
13.2 Hz), 3.78 (s, 3H), 4.55 (dd, 1H, J¼4.5, 9.2 Hz). 13C
NMR (CDCl3, 75 MHz) d: 25.4, 25.6, 27.9; 36.7, 37.8, 38.0,
51.8, 52.4, 56.5, 83.4, 149.6, 172.1, 178.4. MS (ESI) m/z
617.2 [2MþNa]þ (100%), 320.0 [MþNa]þ (22%). Anal.
calcd for C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C,
60.47; H, 7.61; N, 4.83. The enantiomeric excess was
determined to be 99.6% by hplc (Chiracel OD, n-hexane/
2-propanol 99:1, 1 mL min21, T¼358C), by comparison
with a racemic sample obtained by racemization of the (S)-
enantiomer with LDA [Rt (S-enantiomer)¼17.82 min, Rt
(R-enantiomer)¼19.30 min)].
3.1.12. (3S)-1-Methoxy-2-aza-spiro[4,4]nonane-2,3-
dicarboxylic acid 2-tert-butyl ester 3-methyl ester (21).
A 1.0 M solution of lithium triethylborohydride in THF
(6.42 mL, 6.42 mmol) was added to a solution of 20
(1.592 g, 5.35 mmol) in THF (22 mL) at 2788C under a
nitrogen atmosphere. After 45 min the reaction mixture was
quenched with saturated aqueous NaHCO3 (10 mL) and
warmed to 08C. Thirty percent H2O2 (1.0 mL) was added,
and the mixture was stirred at 08C. After 20 min the organic
solvent was removed in vacuo, and the aqueous phase was
extracted with CH2Cl2 (3£15 mL). The combined organic
layers were dried, filtered and evaporated to dryness to give
1.605 g of the corresponding 1-hydroxy derivative as a
70:30 mixture (NMR) of two isomers, that was used without
purification for the next reaction. A sample was purified by
chromatography for characterization (C6H14/AcOEt 7:3).
TLC Rf 0.40 (C6H14/AcOEt 65:35). IR (neat) 3457, 1759,
1
CHCl3). IR (film) 1788, 1753, 1438, 1370 cm21. H NMR
(CDCl3, 400 MHz) d: 1.51 (s, 9H), 1.93 (dd, 1H, J¼5.8,
13.7 Hz), 2.19–2.33 (m, 3H), 2.36–2.45 (m, 2H), 3.78 (s,
3H), 4.48 (dd, 1H, J¼5.8, 9.8 Hz), 5.08 (ddd, 1H, J¼1.5,
3.4, 17.0 Hz), 5.12–5.20 (m, 3H), 5.67–5.80 (m, 2H). 13C
NMR (CDCl3, 75 MHz) d: 28.3, 30.0 (t), 41.4 (t), 41.8 (t),
49.2 (s), 52.9, 56.6, 84.1 (s), 119.8 (t), 120.2 (t), 132.9,
133.2, 149.6 (s), 172.5 (s), 176.8 (s). MS (ESI) m/z 669.1
[2MþNa]þ (20%), 345.9 [MþNa]þ (100%), 246.1 (67%).
Anal. calcd for C17H25NO5: C, 63.14; H, 7.79; N, 4.33.
Found: C, 63.24; H, 7.68; N, 4.44.
3.1.10. (3S)-1-Oxo-2-aza-spiro[4,4]non-7-ene-2,3-dicar-
boxylic acid 2-tert-butyl ester 3-methyl ester (19). To a
0.04 M solution of 6 (2.962 g, 9.16 mmol) in dry CH2Cl2
under nitrogen was added the catalyst 24 (379 mg,
0.46 mmol) and the mixture stirred for 24 h. Lead (IV)
acetate (408 mg, 0.92 mmol) was added and the stirring
continued overnight. The solvent was evaporated and the
crude black residue purified by flash chromatography
(C6H14/AcOEt 77:23) to give 19 (2.245 g, 83%) as a
white solid. Mp 72–738C (white needles from C6H14). TLC
Rf 0.44 (C6H14/AcOEt 7:3). [a]D¼218.0 (c 1.1, CDCl3). IR
1
1703, 1436, 1391 cm21. H NMR (CDCl3, 300 MHz) d:
1.43 (s, 6.3H), 1.49 (s, 2.7H), 1.35–1.74 (m, 7H), 1.98–2.19
(m, 3H), 3.06 (d, 0.7H, J¼3.5 Hz, exchanges with D2O),
3.75 (s, 2.1H), 3.76 (s, 0.9H), 4.19 (dd, 0.7H, J¼7.6,
9.7 Hz), 4.28 (dd, 0.3H, J¼7.9, 9.4 Hz), 4.92 (d, 0.3H,
J¼4.7 Hz), 4.98 (d, 0.3H, J¼4.7 Hz, exchanges with D2O),
5.06 (d, 0.7H, J¼3.5 Hz). 13C NMR (CDCl3, 75 MHz) d: (m
and M indicate a tentative assignment of the major and the
minor isomer, respectively, based on the relative signal
intensities) 24.7 (m), 24.8 (M), 24.9, 25.0, 28.2 (M), 28.4
(m), 31.8 (M), 32.0 (m), 36.2 (M), 36.4 (m), 39.1 (m), 39.8
(M), 52.2 (M), 52.5 (m), 53.6, 58.0 (m), 58.5 (M), 80.9 (M),
81.2 (m), 87.3 (M), 87.7 (m), 153.7 (m), 153.9 (M), 173.6
(M), 174.1 (m). MS (ESI) m/z 322.0 [MþNa]þ. The crude
product derived from the reduction of 20 (1.498 g) was
dissolved in MeOH (50 mlL) and trimethyl orthoformate
(2.93 mL, 26.75 mmol) was added followed by addition of
pyridinium tosylate (200 mg, 0.75 mmol). After stirring for
2 h the solvent was evaporated and the residue treated with
an aqueous saturated solution of NaHCO3 that was extracted
with ether (3£30 mL). The combined organic layers, dried
and evaporated, gave 21 (colorless oil, 1.560 g) with a
diastereomeric ratio .95:5 (only one isomer detected by 1H
1
(nujol) 1779, 1738, 1358, 1318 cm21. H NMR (CDCl3,
300 MHz) d: 1.51 (s, 9H), 2.11 (dd, 1H, J¼4.4, 13.3 Hz),
2.19–2.35 (m, 2H), 2.34 (dd, 1H, J¼9.0, 13.3 Hz), 2.84–
3.01 (m, 2H), 3.79 (s, 3H), 4.58 (dd, 1H, J¼4.4, 9.0 Hz),
5.55–5.61 (m, 1H), 5.61–5.67 (m, 1H). 13C NMR (CDCl3,
75 MHz) d: 27.9, 38.1 (t), 44.9 (t), 45.0 (t), 50.6 (s), 52.5,
56.4, 83.6 (s), 127.9, 128.1, 149.6 (s), 172.0 (s), 177.8 (s).
MS (ESI) m/z 613.0 [2MþNa]þ (17%), 317.9 [MþNa]þ
(100%), 288.3 (44%), 218.1 (65%). Anal. calcd for
C15H21NO5: C, 61.00; H, 7.17; N, 4.74. Found: C, 61.08;
H, 7.24; N, 4.69.
3.1.11. (3S)-1-Oxo-2-aza-spiro[4,4]nonane-2,3-dicar-
boxylic acid 2-tert-butyl ester 3-methyl ester (20). A
solution of 19 (2.120 g, 7.18 mmol) in EtOH (50 mL) was

4510
L. Colombo et al. / Tetrahedron 59 (2003) 4501–4513
(200 MHz) and 13C (75 MHz) NMR). A sample was
purified by chromatography for characterization (C6H14/
AcOEt 85:15). TLC Rf 0.47 (C6H14/AcOEt 8:2).
[a]D¼247.1 (c 1.1, CDCl3). IR (film) 1759, 1710, 1380,
1431, 1367 cm21. 1H NMR (CDCl3, 400 MHz) d: 0.10 and
0.11 (2 s, 9H), 0.97 and 1.01 (2dd, 1H, J¼7.2, 14.6 Hz,
J¼7.6, 14.5 Hz), 1.15–1.96 (m, 12H), 2.22 and 2.25 (2dd,
1H, J¼7.5, 12.4, 7.8, 12.4 Hz), 3.69 (dd, 0.6H, J¼4.4,
11.8 Hz), 3.77 (s, 3H), 3.79 (dd, 0.4H, J¼5.7, 11.1 Hz), 4.36
(dd, 0.4H, J¼7.4, 10.6 Hz), 4.42 (dd, 0.6H, J¼7.8, 10.3 Hz),
4.45–4.53 (m, 0.4H,), 4.68–4.77 (m, 0.6H). 13C NMR
(CDCl3, 50 MHz) d: 1.0, 1.3, 22.0 (t), 24.2 (t), 24.5 (t), 25.1
(t), 27.7 (t), 31.2 (t), 31.5 (t), 34.1 (t), 34.2 (t), 42.2 (t), 42.3
(t), 52.0 (s), 52.1 (s), 58.0, 58.1, 59.1, 63.4, 75.1, 75.9, 152.1
(s), 152.9 (s), 172.6 (s). MS (ESI) m/z 701.0 [2MþNa]þ
(8%), 362.1 [MþNa]þ (100%). Anal. calcd for
C17H29NO4Si: C, 60.14; H, 8.61; N, 4.13. Found: C,
60.39; H, 8.73; N, 4.21.
1
1304 cm21. H NMR (DMSO-d6, 808C, 200 MHz) d: 1.41
(s, 9H), 1.24–1.47 (m, 2H), 1.48–1.71 (m, 5H), 1.77–1.98
(m, 2H), 2.08 (dd, 1H, J¼7.8, 11.8 Hz), 3.35 (s, 3H), 3.66 (s,
3H), 4.20 (dd, 1H, J¼7.8, 10.1 Hz), 4.65 (s, 1H). 13C NMR
(CDCl3, 50 MHz) d: 23.8 (t), 24.0 (t), 27.5, 31.0 (t), 34.6 (t),
38.3 (t), 51.1, 53.2 (s), 54.5, 57.4, 79.3, 93.5, 153.5 (s),
171.9 (s). MS (ESI) m/z 649.0 [2MþNa]þ (9%), 336.0
[MþNa]þ (100%). Anal. calcd for C16H27NO5: C, 61.32; H,
8.68; N, 4.47. Found: C, 61.53; H, 8.49; N, 4.55.
3.1.13. (1S and 1R,3S)-1-Allyl-2-aza-spiro[4,4]nonane-3-
carboxylic acid methyl ester (5a and 5b). To a solution of
the crude 21 (1.560 g), derived from the previous reaction,
in CH2Cl2 (44 mL) at 08C were added allyltrimethylsilane
(3.96 mL, 24.8 mmol) and InCl3 (971 mg, 4.39 mmol).
After 1.5 h the solvent was removed and to the residue was
added water (10 mL), solid Na2CO3 until pH 8–9 and
AcOEt (30 ml). The two phase mixture was filtered on
celitew, washing abundantly with AcOEt. The aqueous
phase was extracted with AcOEt (3£15 mL) and the
combined organic layers dried and evaporated. The crude
reddish residue (1.131 g) was dissolved in THF and treated
with tetrabutylammonium fluoride (1 M solution in THF,
0.65 mL) with stirring for 30 min. The solvent was
evaporated, the residue taken up in a small volume of
water and extracted with AcOEt (3£30 ml). Evaporation of
the combined organic phases gave an oily residue (1.017 g)
that was dissolved in CH2Cl2 (4 mL) and treated at 08C with
trifluoroacetic acid (4 mL). After 2 h stirring at the same
temperature, the volatiles were removed by evaporation and
the residue suspended in a small volume of water to which
solid Na2CO3 was added to pH 8–9. Extraction with AcOEt
(5£15 mL) and CH2Cl2 (2£10 mL) followed by evaporation
gave an oily mixture that, finally, was purified by flash
chromatography (gradient elution, C6H14/AcOEt from 1:1
to 0:100) to give 5a (626 mg) and 5b (102 mg), both as
colorless oils (global yield from 19: 61%). A sample of the
reaction mixture derived from the allylation reaction
(352 mg) was chromatographed (gradient elution C6H14/
AcOEt from 9:1 to 0:100) to give 22a (170 mg), 23 (6:4
ratio of two stereoisomers, 31 mg), and 5a,b (6:4 ratio of
two stereoisomers, 38 mg).
Compound 5a. Colorless oil. TLC Rf 0.28 (C6H14/AcOEt
1:1). [a]D¼218.9 (c 1.0, MeOH). IR (film) 3329, 1742,
1
1589 cm21. H NMR (CDCl3, 400 MHz) d: 1.20–1.31 (m,
1H), 1.49–1.69 (m, 7H), 1.81 (dd, 1H, J¼7.2, 12.6 Hz),
1.93–2.05 (m, 2H), 2.23–2.32 (m, 1H), 2.41 (bs, 1H,
exchanges with D2O), 2.87 (dd, 1H, J¼3.5, 10.5 Hz), 3.72
(s, 3H), 3.79 (dd, 1H, J¼7.3, 8.7 Hz), 5.08 (d, 1H,
J¼10.1 Hz), 5.16 (dd, 1H, J¼1.2, 17.1 Hz), 5.77–5.90 (m,
1H). 13C NMR (CDCl3, 100 MHz) d: 24.4 (t), 25.1 (t), 33.1
(t), 37.0 (t), 37.7 (t) 43.7 (t), 52.5, 53.3 (s), 58.4, 66.2, 117.3
(t), 136.9, 176.3 (s). MS (ESI) m/z 224.1 [MþH]þ. Anal.
calcd for C13H21NO2: C, 69.92; H, 9.48; N, 6.27. Found: C,
69.81; H, 9.65; N, 6.01.
Compound 5b. Colorless oil. TLC Rf 0.40 (C6H14/AcOEt
1:1). [a]D¼þ1.0 (c 1.0, MeOH). IR (film) 3333, 1736,
1
1209 cm21. H NMR (CDCl3, 400 MHz) d: 1.29–1.38 (m,
1H), 1.40–150 (m, 1H), 1.53–1.67 (m, 6H), 1.73 (dd, 1H,
J¼7.7, 12.5 Hz), 1.94–2.04 (m, 1H), 2.14 (dd, 1H, J¼8.5,
12.5 Hz), 2.18–2.26 (m, 1H), 2.40 (bs, 1H, exchanges with
D2O), 3.09 (dd, 1H, J¼3.2, 10.1 Hz), 3.72 (s, 3H), 3.83 (t,
1H, J¼8.2 Hz), 5.05 (d, 1H, J¼10.1 Hz), 5.12 (dd, 1H,
J¼1.4, 17.1 Hz), 5.77–5.90 (m, 1H). 13C NMR (CDCl3,
100 MHz) d: 24.6 (t), 25.2 (t), 32.2 (t), 36.3 (t), 36.6 (t),
44.5 (t), 52.4, 52.9 (s), 57.4, 64.6, 116.8 (t), 137.3, 176.9 (s).
MS (ESI) m/z 224.1 [MþH]þ. Anal. calcd for C13H21NO2:
C, 69.92; H, 9.48; N, 6.27. Found: C, 69.74; H, 9.62; N,
5.98.
3.1.14. (1S)-1-Allyl-2-(2R and 2S)-(2-benzyl-2-benzyl-
oxycarbonylamino-but-3-enoil)-2-aza-spiro[4,4]nonane-
(3S)-3-carboxylic acid methyl ester (25a and 25b). To a
2 M solution of racemic 17 (650 mg, 2.0 mmol) in dry
CH2Cl2 PyBroPw (1.120 g, 2.4 mmol) and DIEA
(0.675 mL, 4.0 mmol) were added under nitrogen and the
solution stirred at room temperature for 2 h. A 1 M CH2Cl2
solution of 5a (232 mg, 1.0 mmol) was then added, followed
by addtion of DMAP (1.0 mmol, 122 mg) and the mixture
was stirred for 4 days. The solvent was evaporated and the
crude directly flash chromatographed (gradient elution,
C6H14/AcOEt from 85:15 to 0:100) to afford pure 25a
(164 mg, 31%), 25b (218 mg, 41%) and unreacted 5a
(30 mg, 13%).
Compound 22a. Colorless oil. TLC Rf 0.49 (C6H6/di-iso-
propyl ether 7:3). [a]D¼242.1 (c 1.0, CDCl3). IR (film)
1
1755, 1697, 1454, 1390 cm21. H NMR (DMSO-d6, 808C,
400 MHz) d: 1.37 (s, 9H), 1.39–1.75 (m, 8H), 1.83 (bt, 1H,
J¼11.0 Hz), 2.06 (dd, 1H, J¼7.8, 12.4 Hz), 2.17–2.38 (m,
2H), 3.58 (bt, 1H, J¼6.3 Hz), 3.66 (s, 3H), 4.14 (dd, 1H,
J¼7.8, 10.2 Hz), 4.98 (d, 1H, J¼9.8 Hz), 5.09 (dd, 1H,
J¼2.0, 17.1 Hz), 5.88–6.00 (m, 1H). 13C NMR (CDCl3,
50 MHz) d: 28.2 (t), 28.9 (t), 33.0, 36.9 (t), 41.9 (t), 43.1 (t),
44.1 (t), 56.5, 57.8 (s), 63.0, 70.6, 83.9 (s), 120.6, 141.6 (t),
158.3 (s), 178.0 (s). MS (ESI) m/z 346.1 [MþNa]þ. Anal.
calcd for C18H29NO4: C, 66.84; H, 9.04; N, 4.33. Found: C,
66.98; H, 8.86; N, 4.42.
Compound 25a. Colorless oil. TLC Rf 0.48 (C6H14/AcOEt
7:3). [a]D¼271.0 (c 0.5, CDCl3). IR (film) 3305, 3062,
1
Compound 23 (6:4 mixture of stereoisomers). Colorless oil.
TLC Rf 0.44 (C6H14/AcOEt 1:1). IR (film) 1748, 1698,
1746, 1729, 1634, 1496, 1450 cm21. H NMR (DMSO-d6,
808C, 400 MHz, mixture of conformers): 1.26–1.44 (m,

L. Colombo et al. / Tetrahedron 59 (2003) 4501–4513
4511
3H), 1.47–1.64 (m, 4H), 1.65–1.75 (m, 1H), 1.81 (bt, 1H,
J¼10.6 Hz), 2.01 (bt, 1H), 2.32 (q, 1H, J¼15.8, 7.8,
7.8 Hz), 2.45–2.56 (bm, 1H), 3.10 (d, 1H, J¼13.6 Hz), 3.63
(s, 3H), 3.68 (d, 1H, J¼13.6 Hz), 4.14–4.25 (bm, 1H), 4.35
(bs, 0.8H), 4.78 (bs, 0.2H), 4.95 (bd, 1H, J¼10.2 Hz), 4.96
(bs, 1H), 5.05 (bd, 1H, d, J¼17.0 Hz), 5.18 (d, 1H,
J¼12.5 Hz), 5.26 (bs, 1H), 5.28 (d, 1H, J¼11.0 Hz),
5.84–6.03 (m, 2H), 6.95–7.02 (m, 1.8H), 7.11–7.26 (m,
3.2H), 7.29–7.45 (m, 6H). 13C NMR (DMSO-d6, 808C,
50 MHz, mixture of conformers): 23.9, 24.6, 32.8, 43.0 (b),
52.1, 60.0 (b), 63.9, 65.3, 66.6, 116,3, 116.9, 126.9, 127.3,
127.4, 128.3, 128.7, 128.8, 128.9, 129.1, 131.8, 137.7,
137.9, 138.4, 155, 3, 170.5, 173.6. MS (ESI) m/z 553.4
[MþNa]þ (66%), 531.1 [MþH]þ (100%). Anal. calcd for
C32H38N2O5: C, 72.43; H, 7.22; N, 5.28. Found: C, 72.09;
H, 7.43; N, 5.45.
(t), 39.2 (t), 40.3 (bt), 52.6, 53.6 (s), 59.6 (s), 60.0, 62.1, 67.4
(t), 126.6, 126.9, 128.5, 128.8, 129.0, 129.3, 131.9, 134.5,
136.7 (bs), 137.1 (s), 153.7 (bs), 169.5 (s), 174.0 (s). MS
(ESI) m/z 525.2 [MþNa]þ (12%), 503.2 [MþH]þ (100%),
352.2 (22%). Anal. calcd for C30H34N2O5: C, 71.69; H,
6.82; N, 5.57. Found: C, 71.78; H, 6.69; N, 5.46.
Compound 26b. White solid: mp 52–548C. TLC Rf 0.41
(C6H14/AcOEt 7:3). [a]D¼252.6 (c 0.6, CDCl3). IR (nujol)
1
3368, 1717, 1639 cm21. H NMR (CDCl3, 400 MHz) d
1.23–1.91 (m, 9H), 2.11 (dd, 1H, J¼7.5, 12.5 Hz), 2.25–
2.38 (m, 1H), 2.42–255 (m, 1H), 3.28 (d, 1H, J¼14.2 Hz),
3.70 (s, 3H), 3.98 (d, 1H, J¼14.2 Hz), 4.33 (bd, 1H,
J¼12.1 Hz), 4.42 (dd, 1H, J¼7.5, 10.0 Hz), 5.07 (d, 1H,
J¼12.5 Hz), 5.20 (d, 1H, J¼12.5 Hz), 5.80 (ddd, 1H, J¼2.3,
6.1, 12.5 Hz), 6.31 (bd, 1H, J¼12.5 Hz), 6.55 (bs, 1H),
6.91–6.98 (m, 2H), 7.12–7.23 (m, 3H), 7.30–7.42 (m, 5H).
13C NMR (CDCl3, 75 MHz) d: 23.8 (t), 24.2 (t), 31.0 (t),
33.6 (t), 37.9 (t), 39.4 (t), 41.8 (t), 52.7, 54.2 (s), 61.1, 64.4
(s), 65.0, 66.4 (t), 127.3, 127.5, 128.3, 128.4, 128.7, 128.8,
129.3, 130.0, 135.8 (s), 137.4 (s), 154.7 (s), 169.8 (s), 173.1
(s). MS (ESI) m/z 525.3 [MþNa]þ (68%), 503.1 [MþH]þ
(100%), 352.2 (29%). Anal. calcd for C30H34N2O5: C,
71.69; H, 6.82; N, 5.57. Found: C, 71.73; H, 6.75; N, 5.50.
Compound 25b. White solid: mp 34–368C. TLC Rf 0.40
(C6H14/AcOEt 7:3). [a]D¼25.5 (c 0.5, CDCl3). IR (nujol)
1
3329, 1782, 1727, 1623 cm21. H NMR (DMSO-d6, 808C,
400 MHz, mixture of conformers) d: 1.19–1.42 (m, 3H),
1.43–1.63 (m, 4H), 1.64–1.77 (m, 1H), 1.83 (dd, 1H,
J¼10.3, 12.4 Hz), 2.00 (dd, 1H, J¼8.3, 12.4 Hz), 2.35–2.41
(m, 2H), 3.00 (d, 0.5H, J¼13.9 Hz), 3.11 (d, 0.5H,
J¼13.7 Hz), 3.29 (d, 0.5H, J¼13.9 Hz), 3.62 (s, 3H), 3.65
(d, 0.5H, J¼13.7 Hz), 3.92 (bs, 1H), 4.39 (bs, 1H), 4.92 (dd,
1H, J¼1.8, 10.4 Hz), 5.05 (dd, 1H, J¼1.8, 17.3 Hz), 4.96–
5.29 (m, 3H), 5.44 (d, 0.5H, J¼10.5 Hz), 5.51 (d, 0.5H,
J¼17.2 Hz), 5.81–6.05 (m, 1.5H), 6.13 (dd, 0.5H, J¼10.5,
17.2 Hz), 6.91–7.03 (m, 1.5H), 7.09–7.25 (m, 4H), 7.25–
7.45 (m, 5.5H). 13C NMR (DMSO-d6, 808C, 50 MHz,
mixture of conformers) d: 22.5 (t), 23.1 (t), 31.6 (t), 36.3 (t),
37.7 (t), 41.4 (t), 41.7 (t), 51.0, 54.9 (s), 58.9, 63.4, 64.0,
65.3 (t), 68.2 (s), 114.9 (t), 115.4 (t), 117.1 (t), 125.1, 127.1,
127.4, 127.7, 127.8, 127.9, 129.8, 130.5, 133.2 (s), 134.5,
137.0, 137.4 (s), 154.2 (s), 169.4 (s), 172.2 (s). MS (ESI) m/z
553.4 [MþNa]þ (100%), 531.1 [MþH]þ (80%). Anal. calcd
for C32H38N2O5: C, 72.43; H, 7.22; N, 5.28. Found: C,
72.51; H, 7.41; N, 5.12.
3.1.16. Methyl (6S and 6R)-6-benzyl-6-{[(benzyloxy)car-
bonyl]amino}-(2S)-5-oxooctahydro-1H-pyrrolo[1,2-
a]azepine-(3S)-3-carboxylate-cyclopentane (1:1) (3a and
3b). To a solution of 26a (143 mg, 0.28 mmol) in MeOH
(2 mL) was added Pd, 10% wt on activated carbon (14 mg),
and stirred under a positive pressure of hydrogen overnight.
After filtration on celitew and careful washing with the same
solvent, the colorless solution was evaporated. The crude
product was purified by flash chromatography (AcOEt/Et3N
95:5) to give pure 3a (88 mg, 83%) as an oil. The same
procedure, applied to 26b (182 mg, 0.36 mmol) gave, after
flash chromatography (AcOEt/Et3N 9:1), 117 mg (87%) of
3b as an oil.
Compound 3a. TLC Rf 0.41 (AcOEt/Et3N 97:3).
[a]D¼241.5 (c 0.6, CDCl3). IR (neat) 3366, 1743,
3.1.15. Methyl (6R and 6S)-6-benzyl-6-{[(benzyloxy)car-
bonyl]amino}-5-oxo-(2S)-2,3,5,6,9,9a-hexahydro-1H-
pyrrolo[1,2-a]azepine-(3S)-3-carboxylate-cyclopentane
(1:1) (26a and 26b). A solution of 25a (231 mg, 0.44 mmol)
and catalyst 12 (13 mg, 0.02 mmol) in 1,2-dichloroethane
(9 mL) was refluxed under nitrogen for 4 h. The solvent was
evaporated and the crude mixture was chromatographed
(C6H14/AcOEt 6:4) to give pure 26a (183 mg, 84%). The
same procedure, applied to 25b (294 mg, 0.55 mmol) gave,
after flash chromatography (C6H14/AcOEt 75:25), 236 mg
(85%) of 26b.
1627 cm21 1H NMR (CDCl3, 400 MHz) d: 1.33–1.80
.
(m, 16H, 14H after exchange with D2O), 1.79 (dd, 1H,
J¼9.4, 12.2 Hz), 1.98 (dd, 1H, J¼7.5, 12.2 Hz), 3.04 (d, 1H,
J¼13.7 Hz), 3.14 (d, 1H, J¼13.7 Hz), 3.78 (s, 3H), 4.43 (dd,
1H, J¼7.5, 9.4 Hz), 4.50 (d, 1H, J¼10.9 Hz), 7.20–7.35 (m,
5H). 13C NMR (CDCl3, 75 MHz) d: 23.3 (t), 24.2 (t), 24.9
(t), 29.3 (t), 33.1 (t), 37.7 (t), 38.8 (t), 39.1 (t), 47.2 (t), 52.6,
53.8 (s), 60.3 (s), 60.8, 65.9, 126.9, 128.4, 132.1, 137.7 (s),
173.7 (s), 174.7 (s). MS (ESI) m/z 741.0 [2MþH]þ (79%),
371.1 [MþH]þ (100%). Anal. calcd for C22H30N2O3: C,
71.32; H, 8.16; N, 7.56. Found: C, 71.43; H, 8.28; N, 7.72.
Compound 26a. White solid: mp 59–618C. TLC Rf 0.32
(C6H14/AcOEt 6:4). [a]D¼2153.8 (c 0.5, CDCl3). IR
.
1H NMR (CDCl3,
Compound 3b. TLC Rf 0.38 (AcOEt/Et3N 9:1).
[a]D¼280.0 (c 0.9, CDCl3). IR (neat) 3362, 3025,
(nujol) 3326, 1722, 1654 cm21
1
400 MHz) d 1.18–1.71 (m, 8H), 1.73–1.89 (bm, 1H),
1.92–2.10 (bm, 1H), 2.12–2.25 (m, 1H), 2.31–2.47 (m,
1H), 3.07 (d, 1H, J¼14.1 Hz), 3.71 (d, 1H, J¼14.1 Hz), 3.78
(s, 3H), 4.47 (dd, 1H, J¼2.8, 12.8 Hz), 4.39–4.53 (bs, 1H),
4.86 (bs, 1H), 5.14 (d, 1H, J¼12.0 Hz), 5.11–5.26 (bs, 1H),
5.70 (dt, 1H, J¼2.3, 12.1 Hz), 5.86 (ddd, 1H, J¼3.0, 4.8,
12.1 Hz), 7.07–7.16 (m, 2H), 7.21–7.50 (m, 8H). 13C NMR
(CDCl3, 75 MHz) d: 23.9 (t), 24.4 (t), 31.7 (t), 33.0 (t), 38.2
1745,1621 cm21. H NMR (CDCl3, 400 MHz) d 0.98 (bs,
1H), 1.28–1.66 (m, 9H), 1.66–1.95 (m, 5H), 1.96–2.05 (m,
3H, 1H after exchange with D2O), 2.88 (bd, 1H,
J¼13.0 Hz), 2.96 (d, 1H, J¼13.0 Hz), 3.17 (bs, 1H), 3.74
(s, 3H), 4.31 (dd, 1H, J¼7.3, 10.1 Hz), 7.14–7.19 (m, 2H),
7.19–7.31 (m, 3H). 13C NMR (CDCl3, 75 MHz) d: 20.6
(bt), 24.0 (t), 24.3 (t), 29.4 (t), 33.1 (t), 33.4 (bt), 38.1 (t),
38.9 (t), 46.4 (bt), 52.7, 53.6 (s), 60.4, 63.4 (s), 64.3 (b),

4512
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127.4, 129.0, 130.7, 136.5 (s), 173.3 (s), 175.0 (s). MS (ESI)
m/z 741.1 [2MþH]þ (94%), 371.2 [MþH]þ (100%). Anal.
calcd for C22H30N2O3: C, 71.32; H, 8.16; N, 7.56. Found: C,
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MURST (COFIN 2000, prot. MM03155477 ‘Synthesis of
mimics and analogs of bioactive natural compounds’) and
University of Pavia are acknowledged for financial support.
The authors thank Professor A. Hoveyda (Boston College)
for the kind gift of catalyst 12, Professor K. Moeller
(Washington University in St. Louis) for providing us with
the spectroscopic data of compounds 8a,b, and Dr L. Belvisi
(University of Milan) for performing molecular mechanics
calculations. We are also grateful to Dr E. Mariotti for his
valuable assistance.
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