Preparation of optically pure fused polycyclic scaffolds by Ugi reaction followed by olefin and enyne metathesis

Article abstract of DOI:10.1016/j.tet.2006.06.061

Optically pure fused polycyclic scaffolds containing up to eight stereocentres have been synthesised by olefin metathesis and tandem enyne metathesis/Diels-Alder addition of Ugi multicomponent reaction adducts generated from 7-oxa-[2.2.1]-bicyclic amino a

Full text of DOI:10.1016/j.tet.2006.06.061

Tetrahedron 62 (2006) 8830–8837
Preparation of optically pure fused polycyclic scaffolds by Ugi
reaction followed by olefin and enyne metathesis
*
Andrea Basso, Luca Banfi, Renata Riva and Giuseppe Guanti
Universitaꢀ degli Studi di Genova, Dipartimento di Chimica e Chimica Industriale, Via Dodecaneso 31, 16146 Genova, Italy
Received 13 April 2006; revised 1 June 2006; accepted 15 June 2006
Available online 24 July 2006
Abstract—Optically pure fused polycyclic scaffolds containing up to eight stereocentres have been synthesised by olefin metathesis and
tandem enyne metathesis/Diels–Alder addition of Ugi multicomponent reaction adducts generated from 7-oxa-[2.2.1]-bicyclic amino acid
derivatives.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
from the symmetric anhydride 1 and using (ꢀ)-2 as chiral
auxiliary.
Multicomponent reactions (MCRs) are a very important
class of reactions, which have recently attracted the attention
of several academic and industrial researchers, due to their
ability to generate quickly and efficiently large collections
of compounds amenable for HTS.1 In this area, the Ugi
four-component reaction occupies a leading position since
it represents a valuable method to access alpha-acylamino-
amides in a straightforward manner.2
R1
H2N
R1
NH2
O
O
O
O
O
O
(1)
O2C
CO2
(-)-(2)
(+)-(2)
R2 NC
R3 CHO
MeOH
The power of this reaction has been dramatically increased
during the last decades by modifications of the classic proce-
dure. Such modifications include the use of non-classical
building blocks, the employment of bifunctional components
or the exploitation of post-condensation modifications. All
these aspects have been extensively reviewed recently by
Doemling.3 Within our research in the field of intramolecular
MCRs, we have recently reported the completely stereo-
selective Ugi 5-Centre-4-Component Reaction (U-5C-
4CR) of an N-alkylated bicyclic b-amino acid derivative 2
with a wide variety of aldehydes and isocyanides;4 and we
have demonstrated that the stereochemistry of the newly gen-
erated carbon centre is governed by the configuration of the
bicyclic unit, which was efficiently prepared in both enantio-
merically pure forms from common substrate 1.5 We have
shown that the bicyclic moiety can be used as a chiral auxili-
ary and that it can be easily removed at the end of the reac-
tion, yielding optically pure amino acid derivatives 4. In
Scheme 1, the reaction sequence is summarised starting
R1
HN
O
R1
N
O
O
R2
R2
N
H
N
H
R3
R3
CO2Me
(3)
(4)
Scheme 1. Optically pure bicyclic amino acid derivatives as chiral auxilia-
ries in stereoselective Ugi reactions.
[2.2.1]-Bicyclic alkenes have been extensively used in intra-
molecular ROM/RCM reactions to construct polycyclic ring
systems, mainly due to the driving force constituted by the
strain release in the ROM step; the conservation of the start-
ing chiral information throughout the process is another
advantage of these transformations.6 However, the final
compounds obtained via this route generally do not display
many additional handles for decorating the framework with
diverse building blocks, a useful feature to render these
scaffolds better suited for structure optimisation studies and
biological screenings. Moreover, the substances used in these
studies are generally available as racemic mixtures, although
an example of ROM/RCM on an optically pure 7-oxa-
[2.2.1]-bicyclic amino acid derivative has been recently
reported.7
* Corresponding author. Fax: +39 010 3536105; e-mail: guanti@chimica.
unige.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.061

A. Basso et al. / Tetrahedron 62 (2006) 8830–8837
8831
On the other hand, the quest for polyfunctional, structurally
complex compounds, acting as smart tools both in under-
standing the role and functions of emerging biological targets
and in validating their biological responses, is becoming
more important in the drug discovery process.8
replacing the inert gas was analysed. Optimal conditions
were found with 10 mol % of the Grubb’s II generation
catalyst
(benzylidene-1,3-bis-(2,4,6-trimethylphenyl)-2-
(imidazolidinylidene)dichloro(tricyclohexylphosphine) ruthe-
nium) under an ethylene atmosphere at a 5 mM concentration
of substrate in dichloromethane (Table 1). The reactions
with and without ethylene did not display a dramatic dif-
ference in reactivity, while the use of Grubb’s I generation
catalyst (benzylidene-bis(tricyclohexylphosphine)dichloro-
ruthenium) resulted in very poor yield of the desired product.
The compounds obtained in this way were fully characterised
and their structure unequivocally determined by two-dimen-
sional NMR experiments. Bicyclic systems have been
recently used as scaffolds to prepare conformationally con-
strained peptides and peptidomimetics.10 We are currently
investigating the properties of these molecules as reverse-
turn inducers in RGD-based peptidomimetic inhibitors of
integrins.11
In this paper, we report our studies on the coupling of the
above-mentioned stereoselective Ugi reaction with two
complexity-generating reactions,9 i.e, ring-opening/ring-
closing metathesis (ROM/RCM) and Diels–Alder addition
to prepare optically pure polycyclic scaffolds.
2. Results and discussion
Optically pure (ꢀ)-N-allyl-3-amino-7-oxa-[2.2.1]-bicyclo-
hept-5-ene-2-carboxylic acid was prepared in good yield us-
ing a procedure similar to that used to prepare N-methyl and
N-benzyl derivatives,5 and reacted with different combina-
tions of aldehydes and isocyanides in methanol at room tem-
perature for 2–4 days (Scheme 2). The resulting Ugi adducts
were isolated in good yields (Table 1) and as a single dia-
stereoisomer, as previously reported for similar compounds.
Optical integrity was previously demonstrated by converting
the amino acids, derived from a retro Diels–Alder process
followed by an enamine deprotection, into the corresponding
Mosher’s amides.5
Compound 7d was further elaborated: after conversion of the
methyl ester into the corresponding allyl ester, conditions for
the ring-closing metathesis between the two terminal double
bonds were investigated. Surprisingly, no product was iso-
lated when the reaction was performed at room temperature,
either with generation (I) or (II) catalyst, and with or without
an ethylene atmosphere. However, while with the generation
(I) catalyst the starting material was recovered unreacted,
with the generation (II) catalyst complete consumption of
compound 7d gave rise to polymerisation products.
O
O
O
R1 NC
NH2
CO2
N
R1
R2 CHO
N
H
The desired tricyclic product 8d was eventually obtained in
a satisfactory 78% yield when the reaction was performed
with the less reactive catalyst (10%) at reflux in a 5 mM
dichloromethane solution under an argon atmosphere. It is
worth noting that a similar reaction was reported by Winkler
and co-workers, but in that case a larger amount of catalyst
(30%) and higher dilution (0.5 mM) were found necessary to
isolate the final product in 57% yield.7
R2
a
CO2Me
(6a-e)
(5)
O
R1
N
H
N
b
O
R2
(7a-e)
CO2Me
In order to increase the diversity of these polycyclic mole-
cules, we also explored the possibility of substituting the
allyl group on the nitrogen atom with a propargyl group,
and to perform the Ugi and the enyne matathesis reactions
on the resulting derivative. Bicyclic amino acid 9 was
therefore reacted with different combinations of aldehydes
and isocyanides and to our surprise stereoselection in this
case was not complete (Scheme 3). At this stage, we cannot
give an explanation of these unexpected results since, if it
can be postulated that a propargyl group, being less bulky
than an allyl group, could in principle have a lower effect
on the stereoselection, it is difficult to use the same rationale
when complete stereoselection is observed with an even less
bulky methyl group.4
O
R1
N
H
N
c, d
R2
O
O
(8d)
O
Scheme 2. Ugi reaction followed by ROM/RCM. Reagents and conditions:
(a) MeOH, room temperature; (b) Grubb’s II generation catalyst, CH2Cl2,
room temperature; (c) allyl alcohol, NaH, room temperature; (d) Grubb’s
I generation catalyst, CH2Cl2, reflux.
The subsequent ROM/RCM step was investigated under
various conditions; in particular, two different catalysts
were tested, and also the presence of an ethylene atmosphere
Table 1. Ugi reaction followed by ROM/RCM
In the case of compound 10b, however, stereoselection was
satisfactory and the major diastereoisomer could be sepa-
rated from the minor one by chromatographic purification.12
This propargyl derivative was then subjected to ROM/RCM
under different conditions (Table 2).
Entry R1
R2
Yield (6) Catalyst Conditions Yield (7)
a
b
c
d
e
f
t-Bu
t-Bu
Bn
Cyclohex i-Pr
t-Bu
t-Bu
i-Bu 61
4-NO2–Ph 70
II
II
II
II
II
I
Ar
Ar
61
71
i-Bu
71
69
46
—
CH2]CH2 88
CH2]CH2 87
CH2]CH2 95
4-Cl–Ph
i-Bu
The reaction did not proceed at all without an ethylene atmo-
sphere, and the starting material was recovered unreacted.
There are many reports in which the presence of ethylene
a
Ar
10
a
See, entry a.

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A. Basso et al. / Tetrahedron 62 (2006) 8830–8837
without the isolation of the diene, by addition of the corre-
O
O
O
sponding alkene; however, due to the high dilution required
for the ROM/RCM process, the Diels–Alder reaction was
found to be extremely slow under these conditions.
NH2 R1 NC
R2 CHO
N
R1
N
H
R2
CO2Me
a
CO2
(10a-b)
(9)
(10a): R1= Bn, R2= i-Bu; r.d. 2:1
3. Conclusions
(10b): R1= t-Bu, R2= 4-Cl-Ph; r.d. 9:1
In conclusion, in the present paper it has been shown how,
starting from simple, easily available precursors, the syn-
thesis of enantiomerically pure fused polycyclic scaffolds
containing up to eight stereocentres can be achieved in
a straightforward manner, taking advantage of a complex-
ity–diversity generating strategybased on a Ugi multicompo-
nent reaction, a ring-opening/ring-closing metathesis and
a Diels–Alder cycloaddition.
O
O
R1
R1
N
H
N
H
N
N
b
R2
CO2Me
O
R2
CO2Me
O
(11b)
(12b)
Scheme 3. Ugi reaction with propargylic amino acid followed by ROM/
RCM. Reagents and conditions: (a) MeOH, room temperature; (b) See text.
Moreover, it is noteworthy that the use of different alde-
hydes, isocyanides and unsaturated moieties on the second-
ary amine in the Ugi reaction, together with the presence of
differently manipulable functionalities on the final adducts,
offers the possibility to diversely decorate these scaffolds
to generate new DOS libraries, useful for application in
chemical genetics.15
Table 2. ROM/RCM on propargylic derivative 10b
Entry Solvent Catalyst Conditions Yield (11b) Yield (12b)
a
b
c
d
e
f
CH2Cl2 II
CH2Cl2
CH2Cl2 II
CH2Cl2
Toluene II
THF II
Ar
Ar
—
—
—
—
26
—
15
8
I
CH2]CH2 64
CH2]CH2 79
CH2]CH2 40a
CH2]CH2 29b
I
With this aim, we are now continuing to work on this
project and the results of this research will be reported in
due course.
a
Twenty percent of open adduct was also isolated.
Seventeen percent of open adduct was also isolated.
b
4. Experimental
gas was found beneficial during enyne metathesis and indeed
also in our case, the reaction proceeded smoothly with the aid
of this gas.13 Interestingly, when the Grubb’s II generation
catalyst was used, two products were isolated: the 6-exo com-
pound 11b and the less common 7-endo compound 12b;14
however, when the Grubb’s I generation catalyst was used in-
stead, only the 6-exo derivative 11b could be isolated in 78%
yield. Other solvents such as toluene and THF were also
investigated, but none of them gave results better than DCM.
4.1. General remarks
TLC analyses have been performed on silica TLC plates
MERCK 60 F254 (0.25 mm thick). Spots have been ob-
served under the UV light (l¼254 nm) or stained with iodine
vapours or with a solution of (NH4)MoO4$4H2O and
Ce(SO4)2 in diluted H2SO4. Flash chromatographies have
been performed on ICN Biomedicals 60A silica (230–
400 mesh). Optical rotations were determined with a Jasco
DP-181 polarimeter, using a Jasco cylindrical cell 10ꢁ
100 mm. Microanalyses were performed on a Heraeus
CHN-O-Rapid instrument. Anhydrous solvents and all
reagents have been bought from FLUKA or ALDRICH.
The diene resulting from this reaction could be further
transformed via a Diels–Alder reaction in the presence of a
dienophile, and representative compounds 13 and 14 were
obtained. Since complete stereocontrol was observed also
during the Diels–Alder reaction, highly complex enantio-
merically pure polycyclic derivatives could be assembled
with this three-step process. Detailed NOE experiments
have been conducted on compound 13, whose structure has
been univocally identified as the one shown in Scheme 4.
The Diels–Alder reaction could be also performed in situ
4.2. NMR spectra
1H NMRs have been recorded on a VARIAN ‘MERCURY
300’ at 300 MHz. Chemical shifts are reported in parts per
million using TMS (0.00 ppm) as internal standard.
H
O
EtOOC
N
N
H
H
O
O
O
O
R1
R1
R1
N
Bn
N
H
N
H
N
H
EtOOC
N
N
N
H
O
a
b
O
R2
CO2Me
O
R2
CO2Me
R2
CO2Me
H
H
(13)
(11b)
(14)
R1= t-Bu, R2= 4-Cl-Ph
Scheme 4. Diels–Alder reactions on bicyclic diene 11b. Reagents and conditions: (a) N-benzylmaleimide, CH2Cl2, room temperature, 78%; (b) Diethylazo-
dicarboxylate, DCM, room temperature, 59%.

A. Basso et al. / Tetrahedron 62 (2006) 8830–8837
8833
J constants are reported in Hertz. 13C NMRs have been re-
corded on a VARIAN ‘MERCURY 300’ at 75 MHz. When
not indicated, spectra have been recorded at room tempera-
ture in CDCl3 as the solvent. Peak attribution is made with
the aid of DEPT, 2D COSY, HSQC and TOCSYexperiments.
116.8 (CH2); 135.5 (CH); 136.0 (CH); 137.1 (CH); 172.2
(C); 172.9 (C).
Elem. Anal. Calcd for: C, 66.64; H, 9.05; N, 7.40. Found C,
66.81; H, 9.04; N, 7.39.
4.3. GC–MS analysis
4.7.2. (1S,2S,3S,4R)-Methyl 3-(N-((R)-(tert-butylcarba-
moyl)(4-nitrophenyl)methyl)-N-allylamino)-7-oxa-bicy-
clo[2.2.1]hept-5-ene-2-carboxylate (6b). M.W. 443.49; Rf
0.34 (eluent: EtOAc/PE 3:7); [a]2D0 ꢀ85.8 (c 1.26, CHCl3).
1H NMR (300 MHz): d 1.40 [9H, s]; 2.98 [1H, t, J 4]; 3.09
[1H, dd, J 15, 8]; 3.42 [1H, d, J 4]; 3.60 [1H, m]; 3.71
[3H, s]; 3.91 [1H, br s]; 4.80 [1H, s]; 5.05 [1H, d, J 4];
5.26 [1H, d, J 10]; 5.32 [1H, d, J 13]; 5.66–5.80 [1H, m];
6.18 [1H, dd, J 6, 1]; 6.29 [1H, dd, J 6, 2]; 7.25 [1H, s];
7.49 [2H, dd, J 7, 2]; 8.24 [2H, dd, J 7, 2].
GC–MS analyses have been performed on an HP-5890 series
II with an HP-1 column (530 mm, length 12 m, internal dia-
meter 0.2 mm). Ultrapure helium has been used as carrier
gas. Mass spectra (electron impact) were recorded on an
HP-5971A spectrometer, coupled to the above chromato-
graph. Conditions for the GC–MS analyses are as follows:
flow: 0.9 mL/min; initial temperature: 100 ꢂC; initial time:
2 min.; rate: 20 ꢂC/min; final temperature: 280 ꢂC; final
time: 4 min; injector temperature: 250 ꢂC.
4.4. General procedure for the Ugi reaction
13C NMR (75 MHz): d 28.4 (CH3); 47.4 (CH); 50.7 (C); 51.2
(CH2); 52.1 (CH3); 63.8 (CH); 65.8 (CH); 78.1 (CH); 80.7
(CH); 118.7 (CH2); 123.3 (CH); 131.2 (CH); 135.4 (CH);
135.5 (CH); 136.1 (CH); 144.5 (C); 147.3 (C); 169.4 (C);
171.7 (C).
The amino acid (0.29 mmol) was suspended in dry methanol
(1 mL), and aldehyde (0.32 mmol) and isocyanide
(0.32 mmol) were added in sequence. The reaction was
stirred at room temperature under nitrogen for 2–5 days,
then concentrated in vacuo and analysed by H NMR to
determine the diastereomeric ratio. The crude material was
then purified by flash chromatography.
1
Elem. Anal. Calcd for: C, 62.29; H, 6.59; N, 9.47. Found C,
62.41; H, 6.60; N, 9.45.
4.7.3. (1S,2S,3S,4R)-Methyl 3-(N-((R)-1-(benzylcarba-
moyl)-3-methylbutyl)-N-allylamino)-7-oxa-bicy-
clo[2.2.1]hept-5-ene-2-carboxylate (6c). M.W. 412.52; Rf
0.47 (eluent: EtOAc/PE 3:7); [a]2D0 ꢀ55.5 (c 0.65, CHCl3).
1H NMR (300 MHz): d 0.91 [3H, d, J 7]; 0.96 [3H, d, J 7];
1.40–1.50 [1H, m]; 1.70–2.00 [2H, m]; 2.80 [1H, t, J 4];
3.26 [1H, d, J 4]; 3.40–3.55 [3H, m]; 3.56 [3H, s]; 4.35
[1H, dd, J 15, 6]; 4.47 [1H, dd, J 15, 6]; 4.86 [2H, br s];
5.09 [1H, dd, J 10, 1]; 5.17 [1H, dd, J 16, 1]; 5.65–5.80
[1H, m]; 6.32 [1H, dd, J 6, 1]; 6.42 [1H, dd, J 6, 1]; 7.20
[1H, br s]; 7.25–7.40 [5H, m].
4.5. General procedure for the ROM/RCM reaction
The bicyclic derivative (0.18 mmol) was dissolved in dry
dichloromethane (30 mL) under argon or ethylene atmo-
sphere. The Grubb’s catalyst (0.018 mmol), dissolved in
dry dichloromethane (6 mL), was added via syringe and
the reaction left stirring overnight. The solvent was then
evaporated under reduced pressure and the crude material
purified by flash chromatography. For compound 8d, the
reaction was performed at reflux.
4.6. General procedure for the Diels–Alder reaction
13C NMR (75 MHz): d 22.5 (CH3); 23.1 (CH3); 25.7 (C);
38.2 (CH2); 43.3 (CH2); 47.4 (CH); 50.2 (CH2); 52.0
(CH3); 59.6 (CH); 64.3 (CH); 78.2 (CH); 82.6 (CH); 117.1
(CH2); 127.3 (CH); 127.8 (CH); 128.6 (CH); 135.8 (CH);
135.9 (CH); 136.8 (CH); 138.6 (C); 172.3 (C); 173.6 (C).
The diene (0.18 mmol) and the dienophile (0.27 mmol) are
dissolved in dry dichloromethane (2 mL) and stirred for
24 h. The solvent is then evaporated and the crude material
purified by flash chromatography.
4.7. Detailed compound characterisation
Elem. Anal. Calcd for: C, 69.88; H, 7.82; N, 6.79. Found C,
69.81; H, 7.80; N, 6.80.
4.7.1. (1S,2S,3S,4R)-Methyl 3-(N-((R)-1-(tert-butylcarba-
moyl)-3-methylbutyl)-N-allylamino)-7-oxa-bicy-
clo[2.2.1]hept-5-ene-2-carboxylate (6a). M.W. 378.51; Rf
0.67 (eluent: EtOAc/PE 3:7); [a]2D0 ꢀ55.4 (c 0.66, CHCl3).
1H NMR (300 MHz): d 0.90 [3H, d, J 7]; 0.94 [3H, d, J 7];
1.33 [9H, s]; 1.40 [1H, m]; 1.65–1.85 [2H, m]; 2.93 [1H, t,
J 4]; 3.31 [1H, d, J 4]; 3.32–3.40 [2H, m]; 3.45 [1H, dd, J
15, 7]; 3.66 [3H, s]; 4.90 [1H, br s]; 5.07 [1H, d, J 4]; 5.11
[1H, dd, J 10, 1]; 5.30 [1H, dd, J 16, 1]; 5.70–5.82 [1H,
m]; 6.34 [1H, dd, J 6, 2]; 6.46 [1H, dd, J 6, 2]; 6.70 [1H, s].
4.7.4. (1S,2S,3S,4R)-Methyl 3-(N-((R)-1-(cyclohexylcar-
bamoyl)-2-methylpropyl)-N-allylamino)-7-oxa-bicy-
clo[2.2.1]hept-5-ene-2-carboxylate (6d). M.W. 390.52; Rf
0.56 (eluent: EtOAc/PE 3:7); [a]2D0 ꢀ37.1 (c 0.52, CHCl3).
1H NMR (300 MHz): d 0.81 [3H, d, J 7]; 0.96 [3H, d, J 7];
1.10–2.50 [11H, m]; 2.66 [1H, d, J 10]; 2.91 [1H, dd, J 4,
3]; 2.99 [1H, dd, J 15, 8]; 3.42 [1H, d, J 3]; 3.60 [3H, s];
3.70–3.90 [2H, m]; 4.85 [1H, br s]; 5.00–5.15 [3H, m];
5.65–5.80 [1H, m]; 6.16 [1H, d, J 8]; 6.32 [1H, dd, J 6, 2];
6.43 [1H, dd, J 6, 2].
13C NMR (75 MHz): d 22.5 (CH3); 23.0 (CH3); 25.7 (CH);
28.6 (CH3); 38.2 (CH2); 47.2 (CH); 50.4 (C); 50.6 (CH2);
51.9 (CH3); 59.8 (CH); 64.3 (CH); 78.5 (CH); 82.8 (CH);
13C NMR (75 MHz): d 19.6 (CH3); 20.1 (CH3); 24.8 (CH2);
24.9 (CH2); 25.5 (CH2); 27.8 (CH); 33.0 (CH2); 33.3 (CH2);

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A. Basso et al. / Tetrahedron 62 (2006) 8830–8837
46.3 (CH); 47.4 (CH); 50.3 (CH2); 51.9 (CH3); 64.0 (CH);
67.9 (CH); 78.6 (CH); 83.6 (CH); 116.0 (CH2); 135.8
(CH); 136.1 (CH); 137.5 (CH); 171.5 (C); 172.6 (C).
13C NMR (75 MHz): d 28.5 (CH3); 51.2 (CH); 51.3 (C); 51.8
(CH3); 52.1 (CH2); 64.9 (CH); 70.6 (CH); 78.4 (CH); 80.7
(CH); 119.4 (CH2); 123.1 (CH); 125.5 (CH); 127.4 (CH);
129.2 (CH); 134.2 (CH); 146.1 (C); 147.3 (C); 167.7 (C);
172.2 (C).
Elem. Anal. Calcd for: C, 67.66; H, 8.78; N, 7.17. Found C,
67.79; H, 8.76; N, 7.16.
GC–MS 12.1 min (100%) [443 (M), 343 (100%, Mꢀt-
BuNHCO), 208 (30%, Mꢀt-BuNHCOCHC6H4NO2), 96
(60%)].
4.7.5. (1S,2S,3S,4R)-Methyl 3-(N-((R)-(tert-butylcarba-
moyl)(4-chlorophenyl)methyl)-N-allylamino)-7-oxa-bi-
cyclo[2.2.1]hept-5-ene-2-carboxylate (6e). M.W. 432.94;
Rf 0.58 (eluent: EtOAc/PE 3:7); [a]2D0 ꢀ64.8 (c 0.80, CHCl3).
Elem. Anal. Calcd for: C, 62.29; H, 6.59; N, 9.47. Found C,
62.37; H, 6.58; N, 9.47.
1H NMR (300 MHz): d 1.38 [9H, s]; 2.95 [1H, t, J 4]; 3.07
[1H, dd, J 15, 8]; 3.36 [1H, d, J 4]; 3.55–3.65 [1H, m];
3.70 [3H, s]; 3.87 [1H, br s]; 4.66 [1H, s]; 5.02 [1H, d, J
4]; 5.24 [1H, d, J 10]; 5.30 [1H, d, J 16]; 5.66–5.80 [1H,
m]; 6.16 [1H, dd, J 6, 2]; 6.24 [1H, dd, J 6, 1]; 7.21 [2H,
d, J 7]; 7.28 [1H, s]; 7.35 [2H, d, J 7].
4.7.8. (2S,3S,3aS,7aR)-Methyl 4-((R)-1-(benzylcarba-
moyl)-3-methylbutyl)-2,3,3a,4,5,7a-hexahydro-2-vinyl-
furo[3,2-b]pyridine-3-carboxylate (7c). M.W. 412.52; Rf
0.66 (eluent: EtOAc/PE 3:7); [a]2D0 +88.8 (c 0.60, CHCl3).
1H NMR (300 MHz): d 0.85 [3H, d, J 7]; 0.89 [3H, d, J 7];
1.40–1.80 [3H, m]; 3.01 [1H, dd, J 8, 6]; 3.20–3.40 [4H,
m]; 3.63 [3H, s]; 4.05–4.15 [1H, m]; 4.43 [1H, dd, J 15,
6]; 4.52 [1H, dd, J 15, 6]; 4.70–4.80 [1H, m]; 5.20 [1H,
dd, J 10, 1]; 5.29 [1H, dt, Jd 16, Jt 1]; 5.60–5.80 [2H,
m]; 5.99 [1H, ddd, J 11, 4, 2]; 7.20–7.40 [5H, m]; 7.50
[1H, br s].
13C NMR (75 MHz): d 28.5 (CH3); 47.4 (CH); 50.5 (C); 51.0
(CH2); 52.1 (CH3); 63.9 (CH); 66.3 (CH); 78.2 (CH); 80.8
(CH); 118.5 (CH2); 128.6 (CH); 131.7 (CH); 133.8 (C);
135.1 (C); 135.2 (CH); 135.9 (CH); 136.6 (CH); 170.3
(C); 171.9 (C).
Elem. Anal. Calcd for: C, 63.81; H, 6.75; Cl, 8.19; N, 6.47.
Found C, 63.97; H, 6.76; Cl, 8.19; N, 6.46.
13C NMR (75 MHz): d 22.0 (CH3); 23.0 (CH3); 24.5 (CH);
37.7 (CH2); 43.2 (CH2); 47.9 (CH2); 52.3 (CH); 52.5
(CH3); 62.0 (CH); 63.9 (CH); 79.8 (CH); 80.9 (CH);
119.3 (CH2); 124.8 (CH); 127.1 (CH); 127.5 (CH); 127.8
(CH); 128.5 (CH); 134.5 (CH); 138.8 (C); 170.6 (C);
173.7 (C).
4.7.6. (2S,3S,3aS,7aR)-Methyl 4-((R)-1-(tert-butylcarba-
moyl)-3-methylbutyl)-2,3,3a,4,5,7a-hexahydro-2-vinyl-
furo[3,2-b]pyridine-3-carboxylate (7a). M.W. 378.51; Rf
0.57 (eluent: EtOAc/PE 2:8); [a]2D0 +86.8 (c 1.26, CHCl3).
1H NMR (300 MHz): d 0.84 [3H, d, J 7]; 0.88 [3H, d, J 7];
1.38 [9H, s]; 1.40–1.80 [3H, m]; 2.83 [1H, dd, J 8, 6]; 3.20–
3.40 [4H, m]; 3.72 [3H, s]; 4.05–4.15 [1H, m]; 4.85 [1H, t,
J 9]; 5.22 [1H, ddd, J 10, 1, 1]; 5.33 [1H, ddd, J 17, 1, 1];
5.60–5.80 [2H, m]; 5.99 [1H, ddd, J 10, 3, 2]; 6.93 [1H, s].
GC–MS 11.1 min (100%) [412 (M), 278 (100%,
MꢀBnNHCO), 91 (30%)].
Elem. Anal. Calcd for: C, 69.88; H, 7.82; N, 6.79. Found C,
70.09; H, 7.84; N, 6.80.
13C NMR (75 MHz): d 22.0 (CH3); 23.1 (CH3); 24.4 (CH);
28.9 (C); 37.8 (CH2); 47.6 (CH2); 51.3 (CH and C); 52.5
(CH3); 62.4 (CH); 64.0 (CH); 79.9 (CH); 80.9 (CH); 119.4
(CH2); 124.7 (CH); 127.8 (CH); 134.6 (CH); 169.6 (C);
173.6 (C).
4.7.9. (2S,3S,3aS,7aR)-Methyl 4-((R)-1-(cyclohexylcar-
bamoyl)-2-methylpropyl)-2,3,3a,4,5,7a-hexahydro-2-vi-
nylfuro[3,2-b]pyridine-3-carboxylate (7d). M.W. 390.52;
Rf 0.65 (eluent: EtOAc/PE 3:7); [a]2D0 +123.0 (c 1.00,
CHCl3).
GC–MS 9.0 min (100%) [378 (M), 278 (100%, Mꢀt-
1H NMR (300 MHz): d 0.81 [3H, d, J 6]; 0.92 [3H, d, J 6];
1.15–2.20 [12H, m]; 3.10–3.30 [4H, m]; 3.63 [3H, s];
3.70–3.80 [1H, m]; 4.08 [1H, br s]; 4.86 [1H, t, J 9]; 5.23
[1H, dd, J 10, 1]; 5.33 [1H, d, J 16]; 5.60–5.80 [2H, m];
5.97 [1H, ddd, J 10, 4, 2]; 6.97 [1H, d, J 7].
BuNHCO)].
Elem. Anal. Calcd for: C, 66.64; H, 9.05; N, 7.40. Found C,
66.62; H, 9.05; N, 7.41.
4.7.7. (2S,3S,3aS,7aR)-Methyl 4-((R)-(tert-butylcarba-
moyl)(4-nitrophenyl)methyl)-2,3,3a,4,5,7a-hexahydro-2-
13C NMR (75 MHz): d 19.9 (CH3); 20.2 (CH3); 24.8 (CH2);
24.8 (CH2); 25.5 (CH2); 26.0 (CH); 32.9 (CH2); 33.8
(CH2); 47.5 (CH2); 48.0 (CH); 52.6 (CH3); 52.9 (CH);
63.6 (CH); 71.5 (CH); 80.0 (CH); 80.8 (CH); 119.4
(CH2); 124.5 (CH); 127.7 (CH); 134.7 (CH); 167.7 (C);
174.0 (C).
vinylfuro[3,2-b]pyridine-3-carboxylate
(7b).
M.W.
443.49; Rf 0.31 (eluent: EtOAc/PE 3:7); [a]2D0 ꢀ48.8 (c
1.56, CHCl3)
1H NMR (300 MHz): d 1.35 [9H, s]; 3.00 [1H, dd, J 11, 10];
3.25 [1H, dd, J 11, 8]; 3.33 [1H, dq, Jd 17, Jq 3]; 3.40–3.55
[1H, m]; 3.52 [3H, s]; 4.20 [1H, s]; 4.31 [1H, m]; 4.74 [1H,
dd, J 10, 8]; 5.19 [1H, dt, Jd 10, Jt 1]; 5.26 [1H, d, J 17]; 5.65
[1H, ddd, J 17, 10, 8]; 5.70–5.80 [1H, m]; 6.07 [1H, br d, J
10]; 6.66 [1H, s]; 7.60 [2H, d, J 9]; 8.17 [2H, d, J 9].
GC–MS 10.4 min (100%) [390 (M), 264 (100%,
MꢀcyclohexNHCO)].
Elem. Anal. Calcd for: C, 67.66; H, 8.78; N, 7.17. Found C,
67.74; H, 8.76; N, 7.18.

A. Basso et al. / Tetrahedron 62 (2006) 8830–8837
8835
4.7.10. (2S,3S,3aS,7aR)-Methyl 4-((R)-(tert-butylcarba-
moyl)(4-chlorophenyl)methyl)-2,3,3a,4,5,7a-hexahydro-
2-vinylfuro[3,2-b]pyridine-3-carboxylate (7e). M.W.
432.94; Rf 0.16 (eluent: EtOAc/PE 2:8); [a]2D0 ꢀ69.6 (c
0.72, CHCl3).
13C NMR (75 MHz): d 22.4 (CH3); 22.7 and 22.9 (CH3);
25.1 and 25.3 (CH); 36.7 and 37.0 (CH2); 38.4 and 38.5
(CH2); 43.2 (CH2); 47.6 and 48.1 (CH); 51.8 and 51.9
(CH3); 60.6 and 61.6 (CH); 63.4 and 64.5 (CH); 71.9 and
72.0 (CH); 78.2 and 81.3 (CH); 78.3 (CH); 81.5 and 82.4
(CH); 127.2 and 127.3 (CH); 127.7 and 127.8 (CH); 128.5
(CH); 135.2 and 135.7 (CH); 136.0 and 136.4 (CH); 138.3
and 138.4 (C); 171.9 and 172.3 (C); 172.5 and 173.1 (C).
1H NMR (300 MHz): d 1.30 [9H, s]; 3.00 [1H, dd, J 12, 10];
3.21 [1H, dd, J 12, 8]; 3.32 [1H, dq, Jd 17, Jq 3]; 3.40–3.50
[1H, m]; 3.48 [3H, s]; 4.04 [1H, s]; 4.20–4.30 [1H, m]; 4.68
[1H, dd, J 10, 8]; 5.15 [1H, d, J 10]; 5.24 [1H, d, J 17]; 5.63
[1H, ddd, J 17, 10, 8]; 5.65–5.75 [1H, m]; 6.05 [1H, br d,
J 10]; 6.32 [1H, s]; 7.30 [4H, m].
Elem. anal. (mixture) calcd for: C, 70.22; H, 7.37; N, 6.82.
Found C, 70.14; H, 7.35; N, 6.83.
4.7.13. (1S,2S,3S,4R)-Methyl 3-(N-((R)-(tert-butylcarba-
moyl)(4-chlorophenyl)methyl)-N-propargylamino)-
7-oxa-bicyclo[2.2.1]hept-5-ene-2-carboxylate (10b). Major
diastereoisomer; M.W. 430.92; Rf 0.32 (eluent: EtOAc/PE
3:7); [a]2D0 ꢀ72.2 (c 0.50, CHCl3).
13C NMR (75 MHz): d 28.5 (CH3); 51.0 (CH); 51.4 (C); 51.8
(CH3); 52.1 (CH2); 65.4 (CH); 71.5 (CH); 77.6 (CH); 80.8
(CH); 119.1 (CH2); 125.7 (CH); 127.8 (CH); 128.3 (CH);
129.9 (CH); 133.7 (C); 134.5 (CH); 136.9 (C); 169.2 (C);
171.7 (C).
1H NMR (300 MHz): d 1.37 [9H, s]; 2.26 [1H, t, J 2]; 3.10
[1H, t, J 4]; 3.36 [1H, dd, J 18, 2]; 3.40 [1H, d, J 4]; 3.66
[1H, dd, J 18, 2]; 3.69 [3H, s]; 4.29 [1H, br s]; 4.77 [1H,
s]; 5.06 [1H, d, J 4]; 6.22 [1H, dd, J 6, 2]; 6.29 [1H, dd,
J 6, 2]; 7.02 [1H, s]; 7.26–7.36 [4H, m].
GC–MS 11.1 min (100%) [332 (40%, Mꢀt-BuNHCO), 208
(50%, Mꢀt-BuNHCOCHC6H4Cl), 96 (100%)].
Elem. Anal. Calcd for: C, 63.81; H, 6.75; Cl, 8.19; N, 6.47.
Found C, 63.71; H, 6.74; Cl, 8.21; N, 6.47.
13C NMR (75 MHz): d 28.4 (CH3); 37.4 (CH2); 47.1 (CH);
51.0 (C); 52.0 (CH3); 64.2 (CH); 68.0 (CH); 72.8 (CH);
78.3 (CH); 80.7 (C); 81.0 (CH); 128.6 (CH); 131.3 (CH);
133.9 (C); 134.6 (C); 135.6 (CH); 136.0 (CH); 169.6 (C);
171.7 (C).
4.7.11. (5aS,6aR,10aS,10bS)-10-((R)-1-(tert-Butylcarba-
moyl)-3-methylbutyl)-5a,6a,9,10,10a,10b-hexahydro-
pyrido[2,3-b]furo[3,2-c]oxepin-1-(3H)-one (8d). M.W.
388.50; Rf 0.16 (eluent: EtOAc/PE 2:8); [a]2D0 +129.0 (c
0.70, CHCl3).
Elem. Anal. Calcd for: C, 64.11; H, 6.32; Cl, 8.23; N, 6.50.
Found C, 64.23; H, 6.31; Cl, 8.21; N, 6.48.
1H NMR (300 MHz): d 0.83 [3H, d, J 7]; 0.95 [3H, d, J 7];
1.15–2.00 [10H, m]; 2.00–2.20 [1H, m]; 2.40 [1H, d, J 10];
3.20–3.40 [4H, m]; 3.75–3.85 [1H, m]; 4.10 [1H, br s]; 4.54
[1H, ddd, J 13, 7, 1]; 4.64 [1H, dd, J 13, 7]; 5.11 [1H, br d,
J 10]; 5.74 [1H, ddd, J 10, 6, 3]; 6.03 [1H, ddd, J 10, 4, 2];
6.10–6.20 [1H, m]; 6.26 [1H, br d, J 10]; 7.46 [1H, d, J 7].
4.7.14. (2S,3S,3aS,7aR)-Methyl 4-((R)-(tert-butylcarba-
moyl)(4-chlorophenyl)methyl)-2,3,3a,4,5,7a-hexahydro-
2,6-divinylfuro[3,2-b]pyridine-3-carboxylate (11b). M.W.
458.98; Rf 0.77 (eluent: EtOAc/PE 4:6); [a]2D0 ꢀ25.5 (c 0.58,
CHCl3).
13C NMR (75 MHz): d 20.0 (CH3); 20.3 (CH3); 24.7 (CH2);
25.6 (2ꢁCH2); 26.7 (CH); 32.8 (CH2); 33.5 (CH2); 47.8
(CH2); 48.0 (CH); 54.2 (CH); 62.4 (CH2); 65.7 (CH); 70.6
(CH); 76.4 (CH); 79.7 (CH); 124.3 (CH); 126.2 (CH);
128.6 (CH); 138.1 (CH); 168.3 (C); 174.2 (C).
1H NMR (300 MHz): d 1.31 [9H, s]; 2.98 [1H, dd, J 12, 10];
3.19 [1H, dd, J 12, 9]; 3.32 [1H, br d, J 16]; 3.47 [3H, s]; 3.72
[1H, br d, J 16]; 4.07 [1H, s]; 4.35 [1H, br d, J 9]; 4.69 [1H,
dd, J 10, 7]; 5.02 [1H, d, J 18]; 5.04 [1H, d, J 11]; 5.14 [1H,
ddd, J 10, 2, 1]; 5.22 [1H, ddd, J 17, 2, 1]; 5.62 [1H, ddd,
J 17, 10, 8]; 6.04 [1H, br s]; 6.26 [1H, dd, J 18, 11]; 6.28
[1H, s]; 7.20–7.40 [4H, m].
GC–MS 11.3 min (100%) [388 (M), 262 (100%,
MꢀcyclohexNHCO), 124 (40%)].
Elem. Anal. Calcd for: C, 68.01; H, 8.30; N, 7.21. Found C,
67.84; H, 8.28; N, 7.22.
13C NMR (75 MHz): d 28.6 (CH3); 51.1 (CH); 51.5 (C); 51.8
(CH2); 51.8 (CH3); 65.8 (CH); 72.0 (CH); 78.4 (CH); 81.1
(CH); 113.7 (CH2); 119.1 (CH2); 126.0 (CH); 128.4 (CH);
129.9 (CH); 133.7 (C); 134.4 (CH); 135.9 (CH); 136.6
(C); 136.9 (C); 169.2 (C); 171.6 (C).
4.7.12. (1S,2S,3S,4R)-Methyl 3-(N-((RS)-1-(benzylcarba-
moyl)-3-methylbutyl)-N-propargylamino)-7-oxa-bicy-
clo[2.2.1]hept-5-ene-2-carboxylate (10a). Mixture of
diastereoisomers; M.W. 410.51; Rf 0.34 (eluent: EtOAc/PE
3:7).
GC–MS 12.3 min (100%) [458 (M); 358 (100%, Mꢀt-
BuNHCO), 234 (70%, Mꢀt-BuNHCOCHC6H4Cl), 122
(90%)].
1H NMR (300 MHz): d 0.90–1.00 [9H, m]; 1.60–1.90 [3H,
m]; 2.15 [0.67H, d, J 2]; 2.18 [0.33H, d, J 2]; 2.84 [0.33H,
t, J 4]; 2.94 [0.67H, t, J 4]; 3.40 [0.67H, d, J 4]; 3.48
[0.33H, d, J 4]; 3.50–3.75 [3H, m]; 3.58 [2H, s]; 3.62 [1H,
s]; 4.30–4.50 [2H, m]; 4.94 [0.67H, d, J 5]; 4.96 [1H, s];
5.06 [0.33H, d, J 5]; 6.25–6.45 [2H, m]; 6.83 [0.33H, t,
J 6]; 7.18 [0.67H, t, J 6]; 7.20–7.35 [5H, m].
Elem. Anal. Calcd for: C, 65.42; H, 6.81; Cl, 7.72; N, 6.10.
Found C, 65.48; H, 6.80; Cl, 7.70; N, 6.12.
4.7.15. (Z,2S,3S,3aS,8aR)-Methyl 4-((R)-(tert-butylcar-
bamoyl)(4-chlorophenyl)methyl)-3,3a,4,5,6,8a-hexa-
hydro-6-methylene-2-vinyl-2H-furo[3,2-b]azepine-

8836
A. Basso et al. / Tetrahedron 62 (2006) 8830–8837
Hj2
3-carboxylate (12b). M.W. 458.98; Rf 0.64 (eluent: EtOAc/
PE 4:6); [a]2D0 ꢀ96.4 (c 0.50, CHCl3).
Hj1
O
Ht2
Ht1
Hg
O
N
1H NMR(300 MHz): d 1.36 [9H, s];2.94 [1H, dd, J 9, 6]; 3.37
[3H, s]; 3.43 [1H, br d, J 15]; 3.60 [1H, dd, J 9, 6]; 3.94 [1H, br
d, J 15]; 4.07 [1H, s]; 4.54 [1H, dd, J 9, 8]; 4.93 [1H, br d, J 9];
4.95 [1H, s]; 5.16 [1H, ddd, J 10, 1, 1]; 5.17 [1H, s]; 5.30
[1H, ddd, J 17, 2, 1]; 5.57 [1H, ddd, J 17, 10, 7]; 5.99 [1H,
br d, J 11]; 6.20 [1H, dd, J 11, 2]; 6.56 [1H, s]; 7.20–7.40
[4H, m].
Hc
Hd
N
Hb
N
H
Hn
O
O
Ha
O
O
Cl
4.7.17. (2S,3S,3aS,9aS,9bR)-Diethyl 4-((R)-(tert-butylcar-
bamoyl)(4-chlorophenyl)methyl)-2,3,3a,4,5,9,10b-hexa-
hydro-3-methoxycarbonyl-2-vinylfuro[3,2-h]pyrido[4,
3-c]pyridazine-8,9(7H,10aH)-dicarboxylate (14). M.W.
633.13; Rf 0.49 (eluent: EtOAc/PE 1:1); [a]2D0 ꢀ104.9 (c
0.35, CHCl3).
13C NMR (75 MHz): d 28.7 (CH3); 51.3 (C); 51.4 (CH3);
55.6 (CH2); 56.4 (CH); 70.8 (CH); 71.2 (CH); 79.3 (CH);
80.5 (CH); 118.6 (CH2); 121.3 (CH2); 128.7 (CH); 131.3
(CH); 131.3 (CH); 132.2 (CH); 133.2 (CH); 134.1 (C);
134.9 (C); 140.5 (C); 169.9 (C); 171.5 (C).
1H NMR (CD3OD, 300 MHz): d 1.20–1.30 [6H, m]; 1.28
[9H, s]; 3.10 [1H, t, J 10]; 3.20–3.60 [5H, m]; 3.47 [3H,
s]; 4.12 [1H, s]; 4.15–4.30 [4H, m]; 4.43 [1H, dd, J 17, 6];
4.60 [1H, t, J 8]; 5.15 [1H, d, J 10]; 5.27 [1H, d, J 17];
5.55–5.70 [1H, m]; 5.68 [1H, br s]; 7.20–7.40 [4H, m];
7.81 [1H, s].
GC–MS 12.5 min (100%) [458 (M); 358 (100%, Mꢀt-
BuNHCO), 234 (50%, Mꢀt-BuNHCOCHC6H4Cl), 125
(100%)].
Elem. Anal. Calcd for: C, 65.42; H, 6.81; Cl, 7.72; N, 6.10.
Found C, 65.28; H, 6.82; Cl, 7.72; N, 6.11.
13C NMR (CD3OD, 75 MHz): d 14.9 (CH3); 28.7 (CH3);
43.4 (CH2); 52.4 (CH); 52.8 (CH3); 57.4 (CH2); 60.1 (C);
63.6 and 64.0 (CH2); 69.5 (CH); 71.0 (CH); 80.8 (CH);
81.6 (CH); 119.0 (CH2); 123.6 (CH); 129.3 (CH); 131.9
(CH); 134.9 (C); 136.2 (CH); 138.2 (C); 156.7 and 157.2
(C); 172.2 (C); 172.7 (C).
4.7.16. (2S,3S,3aS,8S,9R,9aS,9bR)-N-Benzyl-4-((R)-(tert-
butylcarbamoyl)(4-chlorophenyl)methyl)-3-(methoxy-
carbonyl)-2,3,3a,4,5,7,8,9,9a,9b-decahydro-2-vinyl-
furo[3,2-c]isoquinoline-8,9-dicarboximide (13). M.W.
646.18; Rf 0.22 (eluent: EtOAc/PE 3:7); [a]2D0 +60.2
(c 0.60, CHCl3).
GC–MS 17.4 min (100%) [532 (200%, Mꢀt-BuNHCO),
408 (30%, Mꢀt-BuNHCOCHC6H4Cl), 207 (75%), 125
(95%), 95 (100%)].
1H NMR (300 MHz): d 1.36 [9H, s]; 2.05–2.15 [1H, m]; 2.41
[1H, ddd, J 11, 6, 4]; 2.69 [1H, ddd, J 15, 7, 1]; 3.05 [1H, br
d, J 16]; 3.10 [1H, ddd, J 8, 8, 1]; 3.23 [1H, t, J 10]; 3.32 [1H,
d, J 16]; 3.38 [1H, t, J 10]; 3.40 [1H, dd, J 8, 6]; 3.58 [3H, s];
3.94 [1H, s]; 4.51 [1H, d, J 14]; 4.62 [1H, d, J 14]; 4.67 [1H,
t, J 10]; 4.89 [1H, dd, J 10, 8]; 5.22 [1H, d, J 10]; 5.33 [1H, d,
J 17]; 5.57 [1H, br s]; 5.67 [1H, ddd, J 17, 10, 8]; 6.72
[1H, s]; 7.20–7.40 [9H, m].
Elem. Anal. Calcd for: C, 58.81; H, 6.53; Cl, 5.60; N, 8.85.
Found C, 58.63; H, 6.53; Cl, 5.59; N, 8.87.
Acknowledgements
13C NMR (75 MHz): d 25.1 (CH2); 28.6 (CH3); 39.9 (CH);
40.5 (CH); 42.3 (CH2); 42.7 (CH); 49.0 (CH2); 51.5 (C);
52.2 (CH3); 54.8 (CH); 65.5 (CH); 67.8 (CH); 76.9 (CH);
81.2 (CH); 119.3 (CH2); 122.1 (CH); 127.8 (CH); 128.2
(CH); 128.2 (CH); 128.5 (CH); 129.7 (CH); 133.1 (C);
134.5 (CH); 135.7 (C); 136.2 (C); 136.3 (C); 168.1 (C);
173.5 (C); 176.9 (C); 179.0 (C).
The authors gratefully acknowledge MIUR (PRIN04) and
Fondazione San Paolo for financial support and wish to
thank Andrea Galatini for his precious help in the NMR
analyses.
Supplementary data
Complete product characterisation data of all new com-
pounds and detailed NOE experiments for compound 13.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.06.061.
Elem. Anal. Calcd for: C, 66.91; H, 6.24; Cl, 5.49; N, 6.50.
Found C, 67.09; H, 6.23; Cl, 5.50; N, 6.51.
NOE analysis. Given the configurations of Cc and Cd (re-
spectively S and R), the structure is confirmed by a NOESY
signal between Hg and Hc (the two protons are cis, therefore
the configuration of Cg is S) and by the absence of a signal
between Hd and Hn (the two protons are trans, therefore
the configuration of Cn is R).
References and notes
€
1. Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem. 2000, 37,
647.
€
2. Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
€
3. Domling, A. Chem. Rev. 2006, 106, 17.
4. Basso, A.; Banfi, L.; Riva, R.; Guanti, G. Tetrahedron Lett.
2004, 45, 587.
5. Basso, A.; Banfi, L.; Riva, R.; Guanti, G. J. Org. Chem. 2005,
70, 575.
Detailed NOE absorbances Hd–Ht1: 7%; Hd–Hb: 7%; Hd–Ha:
6%; Hg–Hc: strong, overlapped with Hg–Hn; Hg–Hj1: 8%;
Hg–Ht2: 4%. The signals of Hc and Hn are overlapped in
the 1H NMR; it is not possible to determine an NOE absor-
bance between these two protons.

A. Basso et al. / Tetrahedron 62 (2006) 8830–8837
8837
ꢁ €
6. For a review, see: Arjona, O.; Csaky, A. G.; Plumet, J. Eur. J.
(b) Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.;
Scolastico, C. Eur. J. Org. Chem. 1999, 389; (c) Qiu, W.; Gu,
X.; Soloshonok, V. A.; Carducci, M. D.; Hruby, V. J.
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ꢁ €
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ꢁ
15. (a) Spring, R. D. Chem. Soc. Rev. 2005, 34, 472; (b) Lokey,
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