A convergent synthesis of enantiopure bicyclic scaffolds through multicomponent Ugi reaction

Article abstract of DOI:10.1016/j.tet.2007.10.058

An efficient and convergent Ugi synthesis of enantiomerically pure N-acyl-2,5-disubstituted pyrrolidines was coupled with an appropriate secondary transformation to give two series of bicyclic derivatives, namely hexahydro pyrrolo-oxazocinediones and -dia

Full text of DOI:10.1016/j.tet.2007.10.058

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1114e1134
www.elsevier.com/locate/tet
A convergent synthesis of enantiopure bicyclic scaffolds through
multicomponent Ugi reaction
*
Luca Banfi, Andrea Basso, Giuseppe Guanti, Silvia Merlo, Claudio Repetto, Renata Riva
Dipartimento di Chimica e Chimica Industriale, Via Dodecaneso 31, I-16146 Genova, Italy
Received 14 September 2007; accepted 17 October 2007
Available online 22 October 2007
´
Dedicated to Professor Csaba Szantay on the occasion of his 80th birthday
Abstract
An efficient and convergent Ugi synthesis of enantiomerically pure N-acyl-2,5-disubstituted pyrrolidines was coupled with an appropriate
secondary transformation to give two series of bicyclic derivatives, namely hexahydro pyrrolo-oxazocinediones and -diazepinediones.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Multicomponent Ugi reaction; Cyclic imine; Pyrrolidine; Peptidomimetics; Acylation
1. Introduction
Among MCRs, those based on the peculiar reactivity of iso-
cyanides, such as the Ugi8 and the Passerini9 reactions, have
The synthesis of non-aromatic heterocyclic medium-sized
rings, containing at least one nitrogen atom,1,2 or of their bicy-
clic derivatives,3,4 has gained a noticeable importance in the
last decades, as well documented in the literature. In particu-
lar, some of these structures have been used as conformation-
ally constrained peptidomimetics. When joined to small
oligopeptide sequences, they may act as ‘external reverse
turn inducers’5 influencing their three dimensional structure
and hence their complexation with various biological targets.
For example, such systems have been successfully used as
external scaffolds for assembling macrocyclic derivatives
incorporating the RGD sequence, which found application as
inhibitors of integrins.2,4,6
An important aspect, when dealing with new molecules of
potential biological activity, is represented by the possibility
to produce different compounds, characterized by chemical
and/or stereochemical diversity, through a similar protocol.
A possibility for multidiversity generation is represented by
multicomponent reactions (MCRs),7 which are extremely con-
vergent, leading to very complex structures in just one step.
found many interesting applications, also in the industry.10
A
drawback of these reactions is the fact that only acyclic struc-
tures, respectively, a peptide and a depsipeptide, can be ob-
tained at first sight. However, heterocyclic compounds can
be prepared by post-condensation cyclization steps, provided
that the acyclic moiety is endowed with one or two suitably
positioned additional functional groups.11 In this field our
group has reported several new convergent syntheses of
heterocycles just coupling
transformation.2,12,13
a MCR with a secondary
We recently reported in preliminary form the synthesis
of a small library of N-acyl-2,5-disubstituted pyrrolidines 4
through an intramolecular variant of the Ugi reaction employ-
ing pyrrolines 5 as cyclic imines (Scheme 1),14 using various
isocyanides and carboxylic acids. The reaction was found to
be of general scope, affording good to excellent yields in all
cases. By employing a carboxylic acid containing an addi-
tional function R5 a subsequent cyclization is in principle
possible, involving either the protected hydroxymethyl group
or the amide function. The effectiveness of this approach
was already preliminary proved, by synthesizing two diaste-
reomeric lactones 1.14 We now report full details on the syn-
thesis of hexahydro pyrrolo-oxazocinediones 1 and extend
* Corresponding author. Tel.: þ39 010 3536126; fax: þ39 010 3536118.
E-mail address: riva@chimica.unige.it (R. Riva).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.058

L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
1115
H
N
a) 96%
c) 96%
e) 98%
g) 89%
O
X
R1
R3
OH
OAc
*
*
O
O
N
N
O
O
X = O, NH
2 = H, NHP
O
HN
O
O
O
6
7
R
O
O
b) 100%
O
1
2
R2
NHBoc
TBDMSO
TBDMSO
OAc
HO
OAc
H
N
OH
OH
O
*
R1
*
9
8
N
N
R4O
R5
R4O
d) 90%
NH
O
O
3
4
n
R2
OAc
TBDMSO
TBDMSO
OH
N3
N3
10
11
f) 88%
L-glutamic acid
N
R4O
5
TBDMSO
O
N
N3
Scheme 1. Retrosynthetic analysis.
13
12
t
the scope of this general strategy to the preparation of hexahy-
dro pyrrolodiazepinediones 2 and 3.
Scheme 2. (a) Ac2O, Py, rt; (b) AcOH, H2O, rt; (c) BuMe2SiCl, imidazole,
DMAP, THF, rt; (d) (i) MsCl, Et3N, CH2Cl2, ꢀ30 ꢁC; (ii) NaN3, DMF,
65 ꢁC; (e) KOH, MeOH, 0 ꢁC; (f) (COCl)2, DMSO, Et3N, ꢀ78 ꢁC to
ꢀ50 ꢁC; (g) PPh3, THF, 50 ꢁC.
While, to the best of our knowledge, bicyclic derivatives 1
were unknown, there are only three examples of hexahydro
pyrrolodiazepinediones having the basic skeleton of 2 and
3;15e17 however, they showed interesting nootropic activity16
or were studied as inhibitors of aminopeptidase P.17
carboxylic acids or isocyanides, whose structures were chosen
according to our present purpose, that is, the synthesis of bicy-
clic system endowed with further appendages.
2. Results and discussion
Other simpler examples of these Ugi condensations may be
found in our preliminary communication.14 Concerning the iso-
cyanides, we employed commercially available benzylisocya-
nide (entries 1e4) and p-methoxyphenylisocyanide (entry
8)23 and also the ‘convertible’ isocyanides proposed by Ugi (en-
tries 5e6 and 10)24 and Linderman (entry 7),25 which have been
prepared by the reported procedures.26 As carboxylic acids,
apart from benzoic acid (entry 9), we used enantiomerically
pure protected a- and b-aminoacids. They were commercially
available with the exception of the orthogonally protected
2,3-diaminopropanoic acid (entry 4). This compound was
prepared in enantiopure form following a known procedure
involving the Hofmann rearrangement of Boc-L-asparagine.27
The yields ranged from moderate to excellent (Table 1),
while the diastereomeric ratio was always moderate, according
First of all we developed an enantioselective synthesis of the
key intermediate 13 (Scheme 2).14 Toward that goal we started
from L-glutamic acid, which was transformed into compound
6.18 An appropriate choice of protecting groups of the three
alcoholic functionalities permitted an independent manipula-
tion of them, allowing the preparation of azido aldehyde 12 in
excellent yield. The five-membered ring was formed as the
last step through a Staudinger/aza-Wittig reaction19 and com-
pound 13 was isolated in 64% overall yield from 6,20 without
racemization.21
Pyrroline 13 was then submitted to a series of Ugi conden-
sations with various isocyanides and carboxylic acids.22 In
Table 1 we show only the results obtained with functionalized
Table 1
Ugi reactions employing pyrroline 13
R1 NC
H
N
H
N
TBDMSO
R2 CO2H
TBDMSO
R1
R1
N
N
+
O
O
TBDMSO
R2
R2
O
O
N
14a-h
15a-h
13
Entrya
R1eNC
R2eCO2H
Product
Yield % (14/15)
dr (14/15)b
1
2
3
4
5
6
7
8
9
a
PhCH2eNC
PhCH2eNC
Boc-L-Asp(OBn)
Boc-D-Asp(OBn)
Z-b-Ala
14, 15a
14, 15b
14, 15c
14, 15d
14, 15e
14, 15f
14, 15g
14, 15h
14, 15i
85
79
66
52
66
67
47
75
81
66:34
68:32
68:32
64:36
63:37
60:40
65:35
64:36
68:32
PhCH2eNC
PhCH2eNC
MeOCO2CH2CMe2eNC
MeOCO2CH2CMe2eNC
S-(NHZ)CH2CH(NHBoc)eCO2H
Boc-L-Asp(OBn)
Z-L-Asp(OtBu)
Z-b-Ala
(o-CH2OTBDMS)C6H4eNC
( p-OMe)C6H4eNC
MeOCO2CH2CMe2eNC
Z-b-Ala
PheCO2H
All reactions were carried out in MeOH (z0.3 M).
See Section 4.
b

1116
L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
to the general trend observed in the Ugi reaction.7 The prevail-
ing diastereoisomer was always the trans one. The relative
configuration was demonstrated by strong NMR analogies
with a previously prepared simpler analog, whose configura-
tion was proved by chemical correlation.14 Moreover, as
shown later, for most of the compounds 14 and 15 the config-
uration has been further confirmed unambiguously. The sepa-
ration of the two epimers was usually not easy and, in some
cases, even impossible; however, the separation became easier
and more convenient on the corresponding alcohols after
TBDMS removal.
As the first synthetic application of derivatives 14 and 15,
we chose to prepare, through a three-step protocol, bicyclic
oxazocinediones (Scheme 3). The diastereomeric mixture of
14 and 15a was treated with HF to give alcohols 16 and 17,
which were separated and individually transformed into the
corresponding hydroxyacids by hydrogenolysis and then
cyclized by means of PyBOP [(benzotriazolyl-1-oxy)tripyrro-
lidinophosphonium hexafluorophosphate] as condensing agent
under high dilution conditions.
behavior, even if it is clear that the spatial position of the
NHBoc must prevent the formation of the eight-membered
heterocycle. A problem related to structures 20, 21, and 23
is represented by the presence of the lactone, a functional
group not always appropriate for pharmacological applica-
tions, due to potential hydrolytic lability. So we focused our
attention to the preparation of more stable compounds.28
We reasoned that 16 and 17 could be exploited as common
intermediates to prepare N-derivatives, such as diazocine-
diones 26 and 27 (cyclic hydroxamic acids) or 28 and 29 (lac-
tams). The latters are in principle accessible from the formers
by reductive cleavage of the NeO bond (Scheme 4). However,
as recently reported elsewhere,13 we were unable to obtain 26
and 27 by cyclization of the hydroxy hydroxamate under Mit-
sunobu’s conditions. For this reason we turned our attention to
a different protocol, planning to replace the hydroxy group
with a primary amino group to be used only for the formation
of the lactam ring. The nucleophilic displacement of the mesyl-
ate of 16 or 17 by means of sodium azide occurred but sur-
prisingly with epimerization at the neighboring stereocenter.
Starting from 16, we always isolated a z1:1 mixture of diaste-
reomeric products 24; the same happened starting from the cis
counterpart 17. Epimers 24 showed different chromatographic
and spectroscopic properties, compared to products 25 derived
from 17. This outcome demonstrates that epimerization had
involved the stereogenic center near to the azide, probably
as the result of a non-stereoselective eliminationeaddition
process. This prompted us to explore a different strategy.
a) 94% (16,17) and 92%
Bn
TBDMSO
NH
(18,19),separation of
16,17 and 18,19
*
N
O
O
BnO2C
*
HO
NHBoc
NH
*
Bn
14a: trans, from L-Asp
15a: cis, from L-Asp
14b: trans, from D-Asp
15b: cis, from D-Asp
N
O
O
BnO2C
*
NHBoc
16: trans, from L-Asp
17: cis, from L-Asp
18: trans, from D-Asp
19: cis, from D-Asp
N3
N3
NH
NH
Bn
Bn
N
N
NH
*
O
O
Bn
O
O
BnO2C
24
BnO2C
N
O
O
NHBoc
NHBoc
O
b) 20: 86%; 21: 90%;
22: 0%; 23: 81%
*
25
O
NHBoc
20: trans, from L-Asp
21: cis, from L-Asp
22: trans, from D-Asp
23: cis, from D-Asp
HO
HO
NH
NH
Bn
Bn
N
N
O
O
O
O
BnO2C
BnO2C
16
Scheme 3. (a) HF, CH3CN, 0 ꢁC; (b) (i) H2, Pd/C, EtOH, rt; (ii) PyBOP, Et3N,
CH2Cl2 2 mM, reflux.
NHBoc
NHBoc
17
see ref. 13
The diversity that can be achieved by coupling the MCR
with a secondary transformation is not only limited to the
‘scaffold diversity’, but also can be finely tuned from a stereo-
chemical point of view. Actually, the absolute configuration of
13 can be decided by choosing L- or D-glutamic acid as starting
material, whereas the configuration of the aspartic acid deriva-
tive can be decided at will as well. On the other hand, the third
stereogenic center is generated during the Ugi condensation.
The moderate stereoselectivity was not therefore a drawback
because it allows to obtain two diastereomeric products. In
order to increase the stereochemical diversity we synthesized
also 14 and 15b, employing Boc-D-Asp(OBn) and submitted
the deprotected alcohols 18 and 19 to the above described
protocol. Compound 23, coming from 15b, was obtained, al-
though in less satisfactory yield, while its epimer 22 was never
isolated. We do not have a rational explanation for this
NH
NH
*
*
Bn
Bn
N
N
BnO
N
HN
O
O
O
O
O
O
NHBoc
26: trans
27: cis
NHBoc
28: trans
29: cis
Scheme 4. (a) (i) MsCl, Et3N, CH2Cl2, ꢀ30 ꢁC; (ii) NaN3, DMF, 50 ꢁC.
In particular, knowing that the hydroxymethyl group can be
easily oxidized, without epimerization, by the Jones reagent to
the carboxylic moiety,14 we reasoned that the above mentioned
epimerization could have been circumvented by inverting the
position of the carboxylic moiety and the amino group, as
illustrated in Scheme 5. First simple commercially available
Z-b-alanine was used as carboxylic input to give 14 and
15c. Initial attempts to cyclize the aminoacid, obtained by

L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
1117
removal of TBDMS, oxidation of the primary alcohols 30 and
31,29 and deprotection of the amine, with typical condensing
agents used in peptide chemistry such as PyBOP, BOP, etc.,
failed. At the end 34 and 35 were successfully prepared by
refluxing the amino ester, obtained by removing the Z group
heterocycles that has been widely investigated in combinatorial
synthesis, by combining MCRs with secondary transforma-
tions.5,31e33 Moreover, we found that both 38, 39 and 40, 41
can be conveniently transformed into the final diazepinediones
42 and 43, under the same conditions, respectively, by intramo-
lecular aminolysis of an ester and of an imide. Thus it was not
necessary to separate 38 from 40 or 39 from 41: actually, when
the mixture of 38 and 40 or of 39 and 41 was independently
submitted to the hydrogenolysisecyclization protocol, the de-
sired 42 and 43 were obtained with an even higher overall
yield!
Another possibility for gaining access to this kind of scaf-
folds is a cyclization involving the side arm coming from the
isocyanide. By this way the protected hydroxymethyl group
remains available as a handle, allowing further diversity gen-
eration, by joining to it peptidomimetic substructures. Of
course a traditional secondary amide is unsuitable for this
strategy and so we studied the utilization of a so-called ‘con-
vertible isocyanide’, choosing first the carbonate introduced by
Ugi.24 For preliminary optimization studies we employed
model compounds 14 and 15i (Scheme 7). The secondary am-
ide, generated by the attack of the isocyanide to pyrroline 13,
can in principle be converted into the acyl oxazolidinones 44
and 45, by treatment with an alkoxide (tBuOK in the original
paper). Methoxide, delivered during the cyclization, is then re-
sponsible for the acylic nucleophilic displacement on activated
44 and 45 to give methyl esters 46 and 47. In our hands the
Ugi protocol, which has been used only in few cases until
now,33,34 did not work as well as expected. The desired 46
and 47 turned out to be only the minor products (29%), while
the prevailing ones were useless alcohols 48 and 49 (38%). So
we undertook a careful tuning of the reaction conditions. We
found that the formation of the primary alcohol is independent
from the presence of traces of water.35 The best base turned
out to be sodium methoxide, whereas the best carbonate was
the methyl one and rt was better than higher or lower temper-
atures. Finally, the work-up of choice involved the introduc-
tion of 10% aqueous citric acid in the reaction mixture.
t
from 32 and 33, in BuOH in the presence of triethyl-
amine.15,30 This time crucial high dilution conditions (used,
for example, for the preparation of 20, 21, and 23) were unnec-
essary for obtaining the seven-membered ring.
a) 89%,
separation
TBDMSO
ZHN
HO
NH
NH
*
*
Bn of 30,31
Bn
N
N
N
ZHN
O
O
O
O
14c: trans
15c: cis
30: trans
31: cis
b) 32: 75%;
33: 68%
c) 34: 76%;
35: 70%
O
NH
NH
Bn
*
*
Bn
MeO2C
ZHN
N
HN
O
O
O
O
34: trans
35: cis
32: trans
33: cis
Scheme 5. (a) HF, MeCN, rt; (b) (i) Jones oxidation, Me2CO, 0 ꢁC; (ii) CH2N2,
t
THF, 0 ꢁC; (c) (i) H2, Pd/C, MeOH, rt; (ii) BuOH, Et3N, 0.2 M, reflux.
Encouraged by this result we extended our protocol to
compounds 14 and 15d, having two orthogonally protected pri-
mary amines (Scheme 6). Actually, the additional amino group
represents an important feature, since it can be used as a handle
to improve the molecular complexity of the final scaffold. We
were quite surprised when we noticed the formation in compa-
rable amount of two compounds during the oxidation step,
either starting from 36 or 37. We recognized the slightly pre-
vailing products as the desired methyl esters 38 and 39, and
we assigned to the others the structure of the diketopiperazines
of formula 40 and 41. These compounds themselves rep-
resent an interesting new scaffold, belonging to a class of
a) 98%,
separation
TBDMSO
ZHN
HO
NH
NH
*
*
Bn of 36,37
Bn
N
N
ZHN
O
O
O
O
O
14d: trans
15d: cis
36: trans
NHBoc
NHBoc 37: cis
b)
OMe
O
TBDMSO
NH
*
N
O
a) 46,47: 74%;
48,49: 15%
O
Ph
NH
Bn
NH
Bn
14i: trans
15i: cis
O
*
*
MeO2C
ZHN
N
N
+
O
O
N
Boc
ZHN
O
O
O
40: trans (45%)
41: cis (31%)
38: trans (33%)
TBDMSO
TBDMSO
N
*
NHBoc 39: cis (27%)
N
O
c) 42: 48%;
43: 49%
O
c) 42: 65%;
43: 66%
O
Ph
Ph
44: trans
b), c) (one pot)
42: 56% from 36;
43: 46% from 37
45: cis
O
NH
*
Bn
N
HN
O
TBDMSO
OH
OMe
O
NH
*
*
O
+
42: trans
NHBoc 43: cis
N
N
O
O
O
Ph
46: trans
47: cis
48: trans
Scheme 6. (a) HF, MeCN, 0 ꢁC; (b) (i) Jones oxidation, Me2CO, 0 ꢁC;
49: cis
t
(ii) CH2N2, THF, 0 ꢁC; (c) (i) H2, Pd/C, MeOH, rt; (ii) BuOH, Et3N, 0.2 M,
reflux.
Scheme 7. (a) MeONa, MeOH, rt.

1118
L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
Boc
Although the suppression of undesired 48 and 49 was never
possible on this family of compounds, we finally obtained
an acceptable 74% yield of 46 and 47.36 We were, however,
very concerned when we noticed that this protocol was not
well suited for more functionalized Ugi products, such as,
for example, 14, 15e and 14, 15f. For this reason we turned
our attention to a different removable isocyanide, as summa-
rized in Scheme 8.
TBDMSO
NH
O
TBDMSO
N
p-An
p-An
*
*
*
*
*
*
N
N
N
N
a) 56: 85%;
O
57: 55% (73% on
unrec. 15h)
O
O
NHZ
NHZ
14h: trans
56: trans
b) 58: 98%;
59: 87%
15h: cis
57: cis
HO
O
O
TBDMSO
c) 60: 93%;
N
NH
NH
OTBDMS
61: 90%
O
O
60: trans
61: cis
58: trans
59: cis
TBDMSO
ZHN
NH
e) 64: 65%;
65: 73%
d) 62: 51%;
63: 31%
*
a) 77%
N
N
OH
O
H
N
O
O
O
14g: trans
15g: cis
Bn
HO
NH
MeO2C
O
*
N
b)
N
N
NH
NH
O
ZHN
O
O
O
trans: 64 = 34
62: trans
63: cis
50: trans
51: cis
cis: 65 = ent-35
HO
O
O
b)
*
NH3
Scheme 9. (a) Boc2O, Et3N, DMAP, CH2Cl2, rt; (b) (i) H2, Pd/C, MeOH, rt;
t
(ii) BuOH, 0.2 M, reflux; (c) Amberlyst 15, MeOH, rt; (d) (i) PDC, DMF,
rt; (ii) CH2N2, DMF, 0 ꢁC; (e) (i) PDC, DMF, rt; (ii) PhCH2NH2, HATU,
2,4,6-collidine, DMF/CH2Cl2, rt.
ZHN
O
52: trans
53: cis
HO
OMe
O
*
ZHN
O
54: trans
55: cis
slow and we never succeeded to achieve complete conversion
of the starting material. Probably, the relative position of the
substituents on 15h caused such a steric hindrance that par-
tially prevented approaching of the reagent and so competition
of the less reactive NHZ group became more important. More-
over 57 was difficult to separate from its isomer bearing the
N(Boc)Z moiety instead of N(Boc)p-An. Anyway the follow-
ing nucleophilic displacement, by the free amino group, gave
excellent results affording diastereomeric compounds 58 and
59. The protected hydroxymethyl group can be exploited for
further elaborations. We, for example, succeeded in converting
it into amides. Removal of TBDMS was not performed under
the usual conditions, due to the noticeable insolubility of 60
and 61 in any organic solvent and the great affinity for water,
which prevented an extractive work-up. This problem was
solved employing Amberlyst 15, which was easily removed
by filtration together with CaCO3 used for eliminating the
residual acidity. The insolubility prevented also the employ-
ment of Jones oxidation. Under optimized conditions we
performed the oxidation with pyridinium dichromate in
DMF. After reducing the excess of oxidant by addition of solid
sodium metabisulphite, the crude product was filtered on a
silica gel column to remove Cr derivatives, and the resulting
acid was directly coupled with benzylamine or treated with di-
azomethane, always in DMF. The overall moderate yield of
methyl esters 62 and 63 is probably a consequence of employ-
ing unavoidable DMF as solvent. Since coupling of the acid
with benzylamine gave good results, the responsibility cannot
be attributed to the oxidative step. Probably the yield of
methylation may be improved using methods alternative to
CH2N2 such as a coupling under the same conditions used
to prepare 64 and 65. Anyway, the efficient transformation
of 60 and 61 into 64 and 65 discloses the possibility to intro-
duce by the same protocol a series of different nitrogen
derivatives.
Scheme 8. (a) HF, MeCN, 0 ꢁC; (b) concd HCl, MeOH, rt.
The transformation of the secondary amide coming from
the isocyanide into the corresponding methyl ester represents
an example of the unusual nitrogen to oxygen migration of
an acyl group, where the equilibrium is probably driven by
the acid conditions leading to the protonated intermediates
52 and 53.25 Since, in the route from 14 and 15g to 54 and
55, several reactions must occur, we preferred first to deprotect
the alcohols and then submit 50 and 51 to the migration, hav-
ing in mind to test the one-pot procedure only later. Whatever
the reaction conditions we never succeeded in isolating the
desired esters 54 and 55, identifying instead the methyl ester
of Z-b-alanine. The high lability of the tertiary amide is prob-
ably enhanced by the presence of the free hydroxymethyl
group, which assists the cleavage of the NeCO bond, as
previously observed also by Evans.37
We finally turned our attention to the use of an isocyanide,
which gives a secondary amide that can be further activated in
order to undergo an intramolecular transamidation reaction
promoted by the primary amine (Scheme 9), not requiring
therefore the preparation of the methyl ester. A similar strategy
has been previously adopted in the synthesis of pyrroles on
solid phase38 and for cleaving Ugi products from a solid
support.32
On our compounds this strategy gave excellent results on
the trans-14h derivative. Actually, the activation of the aro-
matic secondary amide was achieved by introducing a Boc
group. This transformation was not trivial, due to the compe-
tition of the NHZ group: only after a careful optimization of
the reaction conditions we obtained 56 in excellent yield.
The same did not happen with 15h: on this stereoisomer the
regioselectivity was not so marked and the reaction was rather

L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
1119
Boc-L-Ala
N
Moreover, compounds 64 and 65 gave us also the possibil-
NH
O
ity to unequivocally confirm the relative stereochemistry of the
major part of the scaffolds prepared. Actually, bicyclic deriva-
tives coming from Ugi adducts with trans substituents, pre-
pared either following procedure of Scheme 5 or 9, have to
be identical for symmetry reasons, while the analogous with
cis substituents have to be enantiomers. In our hand, scaffolds
34 and 64 showed the following values of [a]D þ38.4 and
þ37.3, while compounds 35 and 65 gave: þ28.1 and ꢀ25.1,
respectively, thus confirming our hypothesis.
Ph
13 or
67
MTRNH
N
N
H
CO2Me
66
H
NC
R1
NH
O
MTRNH
N
H
N
H
CO2Me
NH
O
R2
from 13:
from 67:
R2
=
R2
=
*
The strategy used for preparing scaffolds 64 and 65 may be
useful, since it offers a real possibility to bind to the pyrroli-
dine nucleus a primary amine (also derived form an amino
acid or a peptide), producing a secondary amide. Although
the same products could be in principle prepared in a more
convergent way starting from a suitable isocyanide and fol-
lowing therefore the strategy described in Schemes 5 and 6,
it should be stressed that peptide or amino ester derived iso-
cyanides cannot be utilized in the Ugi reaction (instead of
benzylisocyanide used to prepare 14, 15c and 14, 15d).
When we attempted to do so, we experienced many troubles.
With isocyanides synthesized from simple chiral a-amino acid
esters the Ugi reaction gave the desired products, but with
complete racemization at the carbon bearing the resulting sec-
ondary amide.39 When the Ugi reaction was performed with
isocyanides derived from dipeptides we observed a sluggish
reaction with the formation of many products. Some of
them have been isolated in modest yield and have been iden-
tified (a few examples are illustrated in Scheme 10). Using
isocyanide 66 with an arginine derived appendage, we noticed
that the carboxylic input is not (or only in part) included
into the products and this behavior do not depend upon the
structure of the imine. When the arginine was replaced by
an unfunctionalized residue (71) a heterocycle such as 72
was isolated. Interestingly the same type of compound (73)
was also isolated when isocyanide 66 was reacted under
non-conventional Ugi conditions.41
Recently 5-aminooxazoles such as 72 and 73 have been
isolated when a tertiary a-isocyanoacetamide (that is, with
a CONR2 group on the carbon a to the NC group) is reacted
with an amine and a carbonyl compound.40 However, the
same behavior has never been reported before with peptide-
derived isocyanides where the a-isocyanoacetamide is
secondary. The formation of these unexpected products can
be explained by the fact that iminium ion 74, one of the inter-
mediates of the reaction that is in equilibrium with its tauto-
mer 75, undergoes an intramolecular nucleophilic attack by
the hydroxy group, instead of reacting with the carboxylate
in an intermolecular fashion. Interestingly, when arginine de-
rived isocyanide 66 was employed, the intramolecular attack
was probably promoted this time by a nitrogen atom of the
guanidine moiety, to give a cyclic adduct that was opened dur-
ing work-up to give 68 or 70 but in both cases the carboxylic
moiety was not incorporated in the final product. The unex-
pected and most of all unpredictable reactivity of these isocya-
nides when submitted to Ugi protocol showed clearly that they
are unsuitable inputs for these MCRs.
N
N
H
Ph
70: 35%
TBDMSO
R3
68: 10% (R3 = H)
69: 13% (R3 = MeCH(NHBoc)CO)
O
R1
N
H
CO2Me
71
NC
R
MeOH
N
Z-Gly
67
CO2Me
N
H
O
NH
66, THF, ZnCl2
72: 37% from 71
73: 65% from 66
Ph
O
OH
R
R
N
H
CO2Me
N
H
CO2Me
N
N
N
H
Ph
N
H
Ph
75
74
Scheme 10. Ugi reaction outcome with isocyanides derived from dipeptides.
3. Conclusions
In this paper we presented a series of secondary transfor-
mations that can be coupled with an efficient and very conver-
gent Ugi reaction. By this protocol we opened the way to
a series of unknown or nearly unknown bicyclic heterocycles.
The same strategy can of course be extended also to more
functionalized systems in order to increase the diversity and
to offer the possibility to decorate them with groups of interest
for interactions with biological targets, such as, for example,
integrins.
4. Experimental
4.1. General
NMR spectra were taken (at rt if not otherwise indicated) in
CDCl3 or DMSO-d6 at 200 or 300 MHz (1H) and 50 or
75 MHz (13C), using TMS as internal standard for CDCl3
spectra. The solvent is specified only for H NMR, meaning
that the same was used also for 13C NMR. Chemical shifts
are reported in parts per million (d scale), coupling constants
1
are reported in hertz. Peak assignment in H NMR spectra
was also made with the aid of double resonance experiments,
gCOSY, and NOESY experiments (bicyclic compounds). In
AB and ABX systems the proton A is considered downfiled
1

1120
L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
and B upfield. Peak assignment in 13C spectra was made with
the aid of DEPT and gHSQC experiments. In many com-
pounds a mixture of rotamers can be identified; therefore
different signals, which can be attributed to the rotamers, are
identified as M (major) and m (minor). Unless otherwise indi-
cated spectra were recorded at rt. GCeMS were carried out on
a HP-5971A instrument, using an HP-1 column (12 m long,
0.2 mm wide), electron impact at 70 eV, and a mass temp of
about 170 ꢁC. Unless otherwise indicated analyses were
performed with a constant He flow of 0.9 ml/min, init. temp¼
100 ꢁC, init. time¼2 min, rate¼20 ꢁC/min, final temp¼260 ꢁC,
final time¼4 min, inj. temp¼250 ꢁC, det. temp¼280 ꢁC. tR are
in minutes. HPLC determinations were carried out on a
HP-1090 instrument equipped with DAD. Columns and condi-
tions are reported in the appropriate section. HPLCeMS
experiments of compounds 42 and 43 were carried out on an
HP-1100 (column Synergi Hydro 150ꢂ3 mm, 4 mm;
H2O$CH3CO2H (0.2%)/CH3CN 30:70, flow 0.5 ml/min,
temp¼35 ꢁC, equipped with an Agilent Ion Trap, source ESI,
nebulizer¼30 psi, dry¼10 l/min, temp¼300 ꢁC, HV capil-
lary¼3200 V, mass range¼50e1300, collision energy¼
2 V. IR spectra were measured with a PerkineElmer 881 instru-
ment as CHCl3 solutions, unless otherwise indicated, and
absorptions are reported in cmꢀ1. Melting points were
187 (Mþ, 29), 145 (11), 127 (5.8), 101 (8.6), 85 (26), 73 (6.7),
72 (24), 67 (48), 59 (7.3), 57 (5.0), 55 (5.9), 43 (100), 42 (11),
1
41 (11), 39 (7.7). H NMR (200 MHz, CDCl3): 1.35 and 1.41
[6H, 2s, C(CH3)2]; 1.55e1.83 [4H, m, (CH2)2CH2OAc]; 2.05
[3H, s, COCH3]; 3.52 [1H, center of m, CHO]; 4.01e4.17
[4H, m, CH2O]. 13C NMR (50 MHz): 20.8 [CH3CO];
24.9 and 25.6 [2C, C(CH3)2]; 26.8 [CH2CH2OAc]; 30.0
[CH2(CH2)2OAc]; 64.1 [CH2OAc]; 69.2 [CHCH2O]; 75.4
[CH]; 108.8 [C(CH3)2]; 170.9 [CO].
4.3. (S )-4,5-Dihydroxypent-1-yl acetate 8
A solution of 7 (18.40 g, 14.75 mmol) in water (330 ml)
was diluted with acetic acid (150 ml) and stirred at rt for
5 h. The solvent was evaporated in vacuo and acetic acid
was azeotropically removed with heptane. The crude was pu-
rified by chromatography with AcOH/MeOH 100:0/96:4 to
give 8 (14.75 g, 100%) as a pale yellow oil. Rf 0.34 (AcOEt/
MeOH 98:2, C). Anal. Found: C, 52.05; H, 8.60. C7H14O4 re-
quires C, 51.84; H, 8.70. [a]2D0 þ2.9 (c 2.04). IR: nmax 3585,
3445, 2949, 1726, 1365, 1193, and 1030. GCeMS (usual
method but starting from 80 ꢁC): tR 5.05; m/z 132 (Mþꢀ40,
0.78), 71 (100), 61 (23), 57 (5.6), 44 (6.2), 43 (87), 42 (8.7),
41 (12). 1H NMR (200 MHz, CDCl3): 1.41e1.94 [4H, m,
(CH2)2CH2OAc]; 2.05 [3H, s, COCH3]; 3.46 and 3.67
[2H, AB part of an ABX system, CH2OH, JAB¼11.2,
JAX¼7.2, JBX¼2.3]; 3.74e3.80 [1H, m, CHO]; 4.12 [2H, t,
CH2OAc, J¼6.4]. 13C NMR (50 MHz): 20.9 [CH3CO]; 24.7
[CH2CH2OAc]; 29.2 [CH2(CH2)2OAc]; 64.3 [CH2OAc];
66.5 [CHCH2O]; 71.6 [CH]; 171.4 [CO].
determined on a Buchi 535 apparatus and are uncorrected.
¨
Values of [a]D were determined on a Jasco DIP 181
polarimeter, in CHCl3 (containing 0.75e1% EtOH) solution,
unless otherwise indicated. TLC analyses were carried out on
silica gel plates, which were developed by these detection
methods: (A) UV; (B) iodine; (C) dipping into a solution of
(NH4)4MoO4$4H2O (21 g) and Ce(SO4)2$4H2O (1 g) in
H2SO4 (31 ml) and H2O (469 ml) and warming; (D) dipping
into a solution of ninhydrin (900 mg), n-butanol (300 ml), and
AcOH (9 ml) and warming. Rf were measured after an elution
of 7e9 cm. Chromatographies were carried out on 220e400
mesh silica gel using the ‘flash’ methodology. Petroleum ether
(40e60 ꢁC) is abbreviated as PE. In extractive work-up, aque-
ous solutions were always re-extracted thrice with the appropri-
ate organic solvent. Organic extracts were washed with brine,
dried over Na2SO4, and filtered, before evaporation of the sol-
vent under reduced pressure. All reactions employing dry sol-
vents were carried out under a nitrogen atmosphere.
4.4. (S )-5-[(tert-Butyldimethylsilyl)oxy]-4-hydroxypent-
1-yl acetate 9
A solution of 8 (8.51 g, 52.47 mmol) in dry THF (100 ml)
was treated with imidazole (8.30 g, 55.10 mmol) and 4-
dimethylamino pyridine (96 mg, 78.58 mmol) and then cooled
to 0 ꢁC. A solution of tert-butyldimethylsilyl chloride
(TBDMS-Cl, 8.31 g, 55.13 mmol) in dry THF (50 ml) was
added via syringe. After 2 h the reaction was stirred at rt for
3 h. In some cases an addition of the reagents (TBDMS-Cl
and imidazole, 0.1 molar equivalents) was required to have
complete reaction of the substrate. After addition of water
(15 ml) the solution was partially concentrated in vacuo and
then partitioned between water and Et2O, and extracted. The
combined organic layers were dried and the solvent was evapo-
rated. The crude was purified by chromatography with PE/Et2O
9:1/4:6 to give 9 (13.93 g, 96%) as a pale yellow oil. Rf 0.44
(PE/Et2O 1:1, C). Anal. Found: C, 56.65; H, 10.35. C13H28O4Si
requires C, 56.48; H, 10.21. [a]2D0 þ2.8 (c 2.98). IR: nmax 2950,
2926, 1726, 1364, 1193, 1091, and 832. GCeMS: tR 6.15; m/z
219 (Mþꢀ57, 0.10), 160 (7.5), 159 (57), 141 (9.2), 131 (9.2),
117 (29), 105 (9.1), 103 (6.0), 89 (12), 85 (21), 77 (11), 76
(7.8), 75 (100), 73 (30), 71 (14), 67 (26), 61 (7.2), 59 (9.2), 58
(5.6), 57 (8.6), 55 (5.3), 47 (6.0), 45 (9.0), 43 (60), 41 (10).
1H NMR (200 MHz, CDCl3): 0.08 [6H, s, Si(CH3)2]; 0.91
[9H, s, C(CH3)3]; 1.41e1.95 [4H, m, (CH2)2CH2OAc]; 2.05
4.2. 3-((S )-2,2-Dimethyl-1,3-dioxolan-4-yl)prop-1-yl
acetate 7
A solution of 6 (15.18 g, 94.75 mmol) in dry pyridine
(40 ml) was treated with acetic anhydride (13.4 ml,
142.16 mmol) and stirred at rt for 1.75 h. The solution was
partitioned between water and Et2O and extracted. The com-
bined organic layers were dried and the solvent was evapo-
rated. Residue pyridine was azeotropically removed with
heptane. The crude was purified by chromatography with
PE/Et2O 100:0/1:1 to give 7 (18.40 g, 96%) as a pale yellow
oil. Rf 0.36 (PE/Et2O 6:4, C). Anal. Found: C, 59.50; H, 8.85.
C10H18O4 requires C, 59.39; H, 8.97. [a]2D0 þ13.2 (c 1.08). IR:
nmax 2981, 1727, 1370, 1191, and 1044. GCeMS: tR 4.91; m/z

L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
1121
[3H, s, COCH3]; 2.46 [1H, br d, OH, J¼3.0]; 3.41 and 3.63 [2H,
AB part of an ABX system, CH2OH, JAB¼10.3, JAX¼7.9,
JBX¼2.8]; 3.62e3.73 [1H, m, CHO]; 4.10 [2H, t, CH2OAc,
J¼6.4]. 13C NMR (50 MHz): ꢀ5.48 and ꢀ5.44 [2C,
Si(CH3)2]; 18.2 [C(CH3)3]; 20.9 [CH3CO]; 24.8
[CH2CH2OAc]; 25.8 [3C, C(CH3)3]; 29.1 [CH2(CH2)2OAc];
64.4 [CH2OAc]; 67.1 [CH2OSi]; 71.3 [CH]; 171.1 [CO].
an ABX system, CH2OSi, JAB¼10.3, JAX¼6.8, JBX¼4.0];
4.09 [2H, t, CH2OAc, J¼6.4]. 13C NMR (50 MHz): ꢀ5.6
[2C, Si(CH3)2]; 18.1 [C(CH3)3]; 20.8 [CH3CO]; 25.3
[CH2CH2OAc]; 25.7 [3C, C(CH3)3]; 26.9 [CH2(CH2)2OAc];
63.2 [CH]; 63.9 [CH2OAc]; 66.2 [CH2OSi]; 171.0 [CO].
4.7. (R)-4-Azido-5-{[(tert-butyldimethylsilyl)-
oxy]pentan}-1-ol 11
4.5. Mosher’s esters (MTPA esters) of 9
A solution of 10 (13.67 g, 45.35 mmol) in MeOH (68 ml)
was cooled to 0 ꢁC and treated with KOH (1 M solution in
MeOH, 68 ml). After 45 min the reaction was quenched with
NH4Cl (aq saturated solution) and concentrated in vacuo. The
residue was extracted with Et2O. The combined organic layers
were dried and the solvent was evaporated. The crude was puri-
fied by chromatography with PE/Et2O 8:2/4:6 to give 11
(11.53 g, 98%) as a pale yellow oil. Rf 0.45 (PE/Et2O 1:1, C).
Anal. Found: C, 51.15; H, 9.55; N, 16.30. C11H25N3O2Si re-
quires C, 50.93; H, 9.71; N, 16.20. [a]2D0 þ26.7 (c 1.95). IR:
nmax 3454, 2987, 2108, 1708, 1191, 1114, and 833. GCeMS:
tR 6.03; m/z 202 (Mþꢀ57, 0.14), 159 (18), 156 (6.6), 144
(8.5), 141 (11), 131 (7.6), 130 (40), 129 (7.1), 128 (10), 127
(12), 116 (5.6), 115 (8.7), 114 (5.1), 101 (9.9), 100 (19), 89
(24), 88 (8.6), 86 (6.3), 85 (6.2), 77 (5.2), 76 (7.9), 75 (100),
74 (11), 73 (50), 70 (9.1), 59 (17), 58 (13), 57 (8.6), 55 (5.9),
A solution of 9 (5.0 mg, 18.09 mmol) in dry CH2Cl2
(500 ml) was cooled to 0 ꢁC and treated with 4-dimethylamino
pyridine (14 mg, 108.52 mmol) and MTPA-Cl (10 ml,
54.26 mmol, either R- or S-chloride). After 10 min the reaction
was stirred at rt for 50 min. The crude was directly purified by
preparative PLC to give the desired MTPA esters in 85e90%
yield. Rf 0.77 (PE/Et2O 1:1, A and C). Selected 1H NMR data
showing the differences between the diastereomeric esters
(200 MHz, CDCl3): (a) S,R ester from S-MTPA-Cl: 3.53
[3H, q, OCH3, J¼1.0]; 3.63 and 3.69 [2H, AB part of an
ABX system, CH2OSi, JAB¼10.9, JAX¼4.5, JBX¼5.7]; 4.06
[2H, br t, CH2OAc, J¼5.8]; 5.13 [1H, center of m, CHOCO];
(b) S,S ester from R-MTPA-Cl: 3.59 [3H, q, OCH3, J¼1.2];
3.73 [2H, apparent d, CH2OSi, J¼5.0]; 3.98 [2H, br t,
CH2OAc, J¼6.0]; 5.17 [1H, br quintuplet, CHOCO, J¼5.6].
1
45 (8.8), 43 (8.4), 41 (10). H NMR (200 MHz, CDCl3): 0.09
4.6. (R)-4-Azido-5-{[(tert-butyldimethylsilyl)oxy]pentyl}
acetate 10
[6H, s, Si(CH3)2]; 0.91 [9H, s, C(CH3)3]; 1.37e1.82 [4H, m,
(CH2)2CH2OH]; 3.33e3.45 [1H, m, CHN3]; 3.59e3.79 [4H,
m, CH2O]. 13C NMR (50 MHz): ꢀ5.6 [2C, Si(CH3)2]; 18.2
[C(CH3)3]; 25.7 [3C, C(CH3)3]; 26.6 [CH2CH2OH]; 29.1
[CH2(CH2)2OAc]; 62.2 [CH2OH]; 63.5 [CH]; 66.4 [CH2OSi].
(a) Mesylate: a solution of 9 (13.93 g, 50.39 mmol) in dry
CH2Cl2 (150 ml) was cooled to ꢀ30 ꢁC and treated with
Et3N (9.1 ml, 65.51 mmol) and MsCl (4.7 ml, 60.47 mmol).
After 1 h the reaction was quenched with NH4Cl (aq saturated
solution), diluted with water to dissolve all the solid and ex-
tracted with Et2O. After drying and solvent removal, crude
mesylate was used as such in the following reaction. Rf 0.48
(PE/Et2O/CH2Cl2 45:10:45, C). (b) Substitution with NaN3:
to a solution of crude mesylate in dry DMF (60 ml) was added
sodium azide (6.56 g, 100.91 mmol) and the suspension was
stirred at 65 ꢁC for 6 h. The crude was partitioned between wa-
ter and Et2O, and extracted. The combined organic layers were
dried and the solvent was evaporated. The crude was purified
by chromatography with PE/Et2O 95:5/8:2 to give 10
(13.67 g, 90%) as a pale yellow oil. Rf 0.82 (PE/Et2O/
CH2Cl2 45:10:45, C). Anal. Found: C, 51.95; H, 9.15; N,
13.80. C13H27N3O3Si requires C, 51.79; H, 9.03; N, 13.94.
[a]2D0 þ25.4 (c 2.59). IR: nmax 2952, 2926, 2104, 1727,
1249, 1113, 1047, and 831. GCeMS: tR 6.66; m/z 273
(Mþꢀ28, 0.087), 159 (5.8), 157 (8.0), 156 (34), 141 (7.5),
130 (9.8), 128 (22), 118 (8.1), 117 (78), 116 (7.4), 115 (17),
114 (5.9), 101 (7.4), 100 (19), 89 (27), 88 (11), 86 (5.6), 85
(5.6), 82 (5.5), 76 (5.4), 75 (66), 73 (66), 67 (11), 61 (6.5),
59 (22), 58 (18), 57 (12), 55 (6.2), 47 (5.6), 45 (15), 43
(100), 42 (7.1), 41 (21), 39 (5.3). 1H NMR (200 MHz,
CDCl3): 0.09 [6H, s, Si(CH3)2]; 0.91 [9H, s, C(CH3)3];
1.38e1.92 [4H, m, (CH2)2CH2OAc]; 2.05 [3H, s, COCH3];
3.31e3.40 [1H, m, CHN3]; 3.63 and 3.73 [2H, AB part of
4.8. (R)-4-Azido-5-[(tert-butyldimethylsilyl)oxy]-
pentanal 12
To a solution of oxalyl chloride (31.3 ml, 66.67 mmol,
2.13 M solution in CH2Cl2) in dry CH2Cl2 (80 ml), previously
cooledtoꢀ78 ꢁC, dry DMSO(7.6 ml, 106.67 mmol)was added.
After 10 min stirring a solution of 12 (11.53 g, 44.45 mmol) in
dry CH2Cl2 (40 ml) was added followed, after 10 min, by
Et3N (26 ml, 186.67 mmol). After2 h thereactionwas quenched
with NH4Cl (aq saturated solution) and extracted with Et2O. The
combined organic layers were dried and the solvent was evapo-
rated. The crude was purified by chromatography with PE/Et2O
75:25/1:1 to give 12 (10.07 g, 88%) as a pale yellow oil. Rf
0.72 (PE/Et2O 1:1, C). Anal. Found: C, 51.35; H, 9.15; N,
16.25. C11H25N3O2Si requires C, 51.33; H, 9.01; N, 16.32.
[a]2D0 þ39.8 (c 2.10). IR: nmax 2952, 2927, 2856, 2738, 2388,
2111, 1722, 1252, 1118, and 833. GCeMS: tR 5.48; m/z 199
(Mþꢀ58, 0.35), 157 (19), 156 (9.7), 154 (5.3), 143 (5.5), 142
(42), 129 (5.7), 128 (26), 127 (6.3), 116 (18), 115 (20), 101
(21), 100 (20), 99 (5.6), 89 (22), 88 (8.8), 84 (5.2), 76 (7.2), 75
(100), 74 (7.5), 73 (50), 59 (21), 58 (12), 57 (8.1), 45 (8.8), 43
(7.4), 41 (8.1). 1H NMR (200 MHz, CDCl3): 0.09 [6H, s,
Si(CH3)2]; 0.91 [9H, s, C(CH3)3]; 1.63e1.94 [2H, m,
CH2CHO]; 2.61 [2H, br t, CH2CH2CHO, J¼7.2]; 3.36e3.48
[1H, m, CHN3]; 3.65 and 3.76 [2H, AB part of an ABX system,

1122
L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
CH2OSi, JAB¼10.6, JAX¼6.9, JBX¼4.0]; 9.80 [1H, t, CHO,
J¼1.2]. 13C NMR (50 MHz): ꢀ5.6 [2C, Si(CH3)2]; 18.1
[C(CH3)3]; 22.8 [CH2CH2CHO]; 25.7 [3C, C(CH3)3]; 40.3
[CH2CHO]; 62.7 [CH]; 66.3 [CH2OSi]; 201.1 [CO].
LC18 250ꢂ4.6 mm, 5 mm, MeOH/H2O 8:2, flow¼1 ml/min,
DAD 220, tR 13.56 (14a) and 14.98 (15a) min]. Compound
14a: Rf 0.40 (CH2Cl2/AcOEt 8:2þ0.5% MeOH, A and C).
[a]2D0 þ28.7 (c 2.10). IR: nmax 3425, 2951, 2926, 1727,
1649, 1245, 1157, and 1109. GCeMS: unsuitable for this anal-
1
4.9. (R)-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-3,4-
dihydro-2H-pyrrol 13
ysis. H NMR (200 MHz, DMSO-d6, rt: 71:30 mixture of ro-
tamers): ꢀ0.001 and 0.02 [6H, 2s, Si(CH3)2]; 0.84 and 0.85
[9H, 2s, SiC(CH3)3]; 1.33 and 1.35 [9H, s, OC(CH3)3];
1.67e2.86 [6H, m, CH2 pyrrolidine, CH2CO2Bn]; 3.23e4.88
[7H, m, CH2Ph, CH2OSi, 3CH]; 4.82 and 4.91 (m) [2H, AB
system, OCH2Ph, J¼12.8]; 5.03 and 5.09 (M ) [2H, AB sys-
tem, OCH2Ph, J¼12.6]; 7.16e7.35 [11H, m, aromatics,
NHBoc (at 100 ꢁC: br s at 6.74)]; 8.11 (m) [1H, br t,
NHCH2Ph, J¼5.3 (at 100 ꢁC: br s at 7.82)]; 8.71 (M ) [1H,
br t, NHCH2Ph, J¼5.5 (at 100 ꢁC: br s at 8.38)]. 13C NMR
(50 MHz): ꢀ5.7, ꢀ5.63, and ꢀ5.58 [2C, Si(CH3)2]; 17.8
[C(CH3)3]; 24.7 (M ) and 26.7 (m), 27.0 (m) and 30.1 [2C,
CH2 pyrrolidine]; 25.6 (m) and 25.7 (M ) [3C, SiC(CH3)3];
28.0 [3C, OC(CH3)3]; 35.1 (M ) and 36.1 (m) [CH2CO2Bn];
41.8 (m) and 42.2 (M ) [NHCH2Ph]; 48.4 (m) and 48.8 (M )
[CHNHBoc]; 58.3 (m) and 59.2 (M ), 60.2 (M ) and 60.4 (m)
[2C, CH pyrrolidine]; 61.6 (M ) and 63.5 (m), 65.3 (M ) and
65.4 (m) [2C, CH2O]; 78.0 (M ) and 78.6 (m) [OC(CH3)3];
126.5, 126.6, 126.7, 127.0, 127.5, 127.7, 127.8, 128.1,
128.15, and 128.22 [10C, aromatic CH]; 135.8 (m) and
136.0 (M ), 138.9 (M ) and 139.3 (m) [2C, aromatic C];
155.0 (M ) and 155.2 (m) [CO (Boc)]; 169.1, 169.9, 170.0,
170.4, 171.2, and 171.8 [3C, CO (amide, lactone)]. Compound
15a: Rf 0.23 (CH2Cl2/AcOEt 8:2þ0.5% MeOH, A and C).
[a]2D0 ꢀ35.8 (c 3.14). IR: nmax 3421, 3005, 2954, 1721,
1655, 1292, 1188, 1161, 1094, and 811. GCeMS: unsuitable
To a solution of 12 (6.94 g, 26.96 mmol) in dry THF
˚
(60 ml) freshly activated 4 A powdered molecular sieves
(520 mg) were added. After stirring for 15 min at rt, PPh3
(8.49 g, 32.35 mmol) was added portionwise. After evolution
of nitrogen finished, the reaction was stirred at 50 ꢁC for
5 h. The sieves were filtered and the resulting solution was
concentrated and directly purified by chromatography with
PE/Et2O 1:1/3:7 to give 13 (5.12 g, 89%) as a pale yellow
oil.20 Rf 0.52 (PE/Et2O 2:8, A and C). Anal. Found: C,
61.80; H, 10.80; N, 6.70. C11H23NOSi requires C, 61.91; H,
10.86; N, 6.56. [a]D20 ꢀ73.3 (c 1.98, CH2Cl2). IR: nmax 2951,
2928, 2855, 1190, 1113, and 717. GCeMS: tR 3.77; m/z 213
(Mþ, 0.12), 198 (5.5), 158 (8.5), 157 (28), 156 (100), 154
(8.3), 100 (6.0), 89 (21), 82 (5.3), 75 (34), 73 (41), 59 (19),
58 (7.9), 57 (5.3), 55 (8.1), 47 (8.1), 45 (13), 43 (8.0), 41
1
(17), 39 (8.1). H NMR (200 MHz, CDCl3): 0.04 and 0.06
[6H, 2s, Si(CH3)2]; 0.88 [9H, s, C(CH3)3]; 1.56e2.64 [4H,
m, CH2CH2]; 3.65 and 3.76 [2H, AB part of an ABX system,
CH2OSi, JAB¼10.2, JAX¼6.9, JBX¼4.0]; 4.12e4.23 [1H, m,
CHCH2O]; 7.61 [1H, br s, CH]N]. 13C NMR (50 MHz):
ꢀ5.42 and ꢀ5.37 [2C, Si(CH3)2]; 18.2 [C(CH3)3]; 23.0
[CH2CH2CHN]; 25.9 [3C, C(CH3)3]; 37.1 [CH2CHN]; 65.7
[CH2OSi]; 74.5 [CH]; 167.4 [CH]N].
1
for this analysis. H NMR (200 MHz, DMSO-d6, rt: 78:22
4.10. General procedure for the Ugi reaction with 13
mixture of rotamers) at 100 ꢁC: 0.03 [6H, s, Si(CH3)2]; 0.87
[9H, s, SiC(CH3)3]; 1.39 [9H, s, OC(CH3)3]; 1.82e2.21 [4H,
m, CH2 pyrrolidine]; 2.68 and 2.79 [2H, AB part of an ABX
system, CH2CO2Bn, JAB¼16.4, JAX¼7.5, JBX¼6.2]; 3.52e
4.75 [7H, m, CH2Ph, CH2OSi, 3CH]; 5.05 [2H, s, OCH2Ph];
6.85 [1H, br s, NHBoc (at rt: 2d at 7.10, J¼7.6 and 7.48,
J¼7.2)]; 7.21e7.35 [10H, m, aromatics]; 7.83 [1H, br s,
NHCH2Ph (at rt: 2br s at 8.10 and 8.32)]. 13C NMR
(50 MHz): ꢀ5.7 and ꢀ5.6 [2C, Si(CH3)2]; 17.9 [C(CH3)3];
25.7 [3C, SiC(CH3)3]; 26.7, 26.9, and 29.6 [2C, CH2 pyrroli-
dine]; 28.0 [3C, OC(CH3)3]; 36.2 [CH2CO2Bn]; 41.8 (M ) and
42.6 (m) [NHCH2Ph]; 48.1 (M ) and 49.2 (m) [CHNHBoc];
58.9 (M ) and 59.8 (m), 60.4 (M ) and 61.0 (m) [2C, CH pyrro-
lidine]; 63.0 (M ) and 63.6 (m), 65.5 [2C, CH2O]; 78.4 (M )
and 78.5 (m) [OC(CH3)3]; 126.5, 126.7, 127.0, 127.7, 127.9,
128.1, 128.2, and 128.3 [10C, aromatic CH]; 135.8, 139.0
(m), and 139.2 (M ) [2C, aromatic C]; 155.0 [CO (Boc)];
169.9, 170.1, 170.8, and 171.3 [3C, CO].
A solution of 13 in dry MeOH (z0.3 M) was treated with
the appropriate carboxylic acid and isocyanide (1.1e1.2 M
equiv). The solution was stirred at rt until complete [usually
1e2 h, but up to 5 h (entries 4e7, Table 1)] and then diluted
with AcOEt. This solution was washed with NaHCO3 (5%
aqueous solution) and brine. After drying, the solvent was
evaporated and the crude was directly chromatographed. We
not always succeeded in the separation of the two diastereoiso-
mers; this was, however, always possible on the corresponding
alcohols. Therefore, for preparative purposes, we preferred to
separate the diastereoisomers after TBDMS removal. More-
over, since pyrrolidines such as 14 and 15 and their derivatives
are involved in several conformational equilibria, the NMR
spectra are often very complex, even at 90e120 ꢁC, and there-
fore not always a complete characterization was possible. On
the contrary, in bicyclic derivatives, the conformational equi-
libria disappeared or were less crucial and the final compounds
have been fully characterized.
4.10.2. Compounds 14 and 15b
Chromatography with PE/AcOEt 7:3/1:1þ0.5% MeOH
gave 14 and 15b as an unseparable mixture (white foam) in
79% overall yield. dr: 62:38 by weight after chromatographic
separation of the corresponding alcohols 18 and 19. Compound
14b:Rf 0.46(PE/AcOEt 6:4þ0.5% MeOH, A andC). Compound
4.10.1. Compounds 14 and 15a
Chromatography with CH2Cl2/AcOEt 8:2/7:3þ0.5%
MeOH gave 14a as a colorless gum and 15a as a white
foam in 85% overall yield. dr: 66:34 [HPLC: column Supelco

L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
1123
15b: Rf 0.40 (PE/AcOEt 6:4þ0.5% MeOH, A and C). These
s, NHCH2Ph (at rt: br t at 8.62, J¼5.7)]. 13C NMR
(75 MHz): ꢀ5.6 (m), ꢀ5.53 (M ), ꢀ5.51 (M ), and ꢀ5.4 (m)
[2C, Si(CH3)2]; 17.80 (M ) and 17.84 (m) [C(CH3)3]; 25.1
(M ), 26.8 (m), 27.5 (m), and 30.0 (M ) [2C, CH2 pyrrolidine];
25.7 [3C, SiC(CH3)3]; 34.0 (m) and 34.2 (M ) [NCOCH2]; 36.4
(M ) and 37.0 (m) [CH2NHZ]; 41.8 (m) and 42.2 (M )
[NHCH2Ph]; 58.9 (m) and 59.0 (M ), 60.3 (m) and 60.5 (M )
[2C, CH pyrrolidine]; 61.9 (M ) and 64.2 (m) [CH2OSi];
65.2 [OCH2Ph]; 126.5, 126.8, 127.1, 127.68, 127.71, 128.1,
and 128.3 [10C, aromatic CH]; 137.1, 139.2 (M ) and 139.5
(m) [2C, aromatic C]; 155.9 (M ) and 156.0 (m) [CO (Z)];
169.7, 171.8, and 172.0 [2C, CO].
compounds have been characterized after TBDMS removal.
4.10.3. Compounds 14 and 15c
Chromatography with PE/AcOEt 6:4/0:100 gave 14c and
15c both as yellow oils in 66% overall yield. dr: 68:32 [HPLC:
column Hypersil ODS 200ꢂ2.1 mm, 5 mm, MeOH/H2O
73:27, flow¼0.4 ml/min, tR 12.45 (14c) and 14.05 (15c)
min; GCeMS: usual method but with final temp¼290 ꢁC, tR
11.79 (15c) and 12.16 (14c) min. Compound 14c: Rf 0.26
(PE/AcOEt 1:1, A and C). [a]2D0 þ13.2 (c 1.68). IR: nmax
3440, 3000, 1711, 1421, 1361, 1224, and 1111. GCeMS
(usual method but with final temp¼290 ꢁC): tR 12.16; m/z
445 (Mþꢀ108, 0.42), 389 (15), 388 (56), 215 (6.7), 214
(36), 204 (6.3), 203 (44), 199 (7.9), 198 (16), 185 (7.5), 179
(27), 157 (8.1), 156 (48), 106 (11), 100 (7.9), 99 (6.1), 98
(8.8), 92 (7.9), 91 (100), 89 (6.3), 82 (26), 80 (7.3), 77
(5.2), 75 (28), 73 (41), 70 (18), 69 (7.9), 68 (18), 65 (6.9),
4.10.4. Compounds 14 and 15d
Chromatography with PE/AcOEt 6:4/45:55 gave 14 and
15d as an unseparable mixture (yellow foam) in 52% overall
yield. dr: 64:36 [HPLC: column Daicel 250ꢂ4.6 mm, hexane/
iPrOH 85:15, flow¼1 ml/min, DAD 220 nm, tR 4.80 (14d) and
7.98 (15d) min]. Compounds 14 and 15d: Rf 0.35 (PE/AcOEt
1
59 (12), 57 (5.9), 56 (17), 55 (18), 42 (5.4), 41 (9.2). H
1
NMR (300 MHz, DMSO-d6, rt: four rotamers can be detected
with the two highly prevailing in a 59:41 ratio) at 90 ꢁC: 0.04,
0.05, and 0.06 [6H, 3s, Si(CH3)2]; 0.88 and 0.89 [9H, 2s,
SiC(CH3)3]; 1.86e2.66 [6H, m, CH2 pyrrolidine, NCOCH2];
3.28 [2H, br dd, CH2NHZ, J¼12.6, 6.6]; 3.54 [1H, br t,
CHCH2OSi, J¼9.3]; 3.51e4.43 [5H, m, CHCO, CH2OSi,
NHCH2Ph]; 5.04 [2H, s, OCH2Ph]; 6.76 [1H, br s, NHZ];
7.19e7.39 [10H, m, aromatics]; 8.01 (M ) [1H, br s, NHCH2Ph
(at rt: br t at 8.26, J¼6.0)]; 8.30 (m) [1H, br s, NHCH2Ph (at rt:
br t at 8.54, J¼5.8)]. 13C NMR (75 MHz) (only the signals of
the two highly prevailing rotamers have been reported): ꢀ5.6
(m), ꢀ5.5 (M ), ꢀ5.4 (M ), and ꢀ5.3 (m) [2C, Si(CH3)2]; 17.9
(M ) and 18.0 (m) [C(CH3)3]; 25.7 [3C, SiC(CH3)3]; 26.0 (m),
26.9 (M ), 27.1 (M ), and 29.6 (m) [2C, CH2 pyrrolidine]; 33.6
(M ) and 33.7 (m) [NCOCH2]; 36.3 (m) and 36.8 (M )
[CH2NHZ]; 41.8 (M ) and 42.2 (m) [NHCH2Ph]; 59.2 (m)
and 59.4 (M ), 60.1 (M ) and 60.5 (m) [2C, CH pyrrolidine];
62.3 (m) and 63.2 (M ) [CH2OSi]; 65.2 [OCH2Ph]; 126.6,
126.8, 127.0, 127.7, 128.1 and 128.3 [10C, aromatic CH];
137.1, 139.1 (m) and 139.4 (M ) [2C, aromatic C]; 155.9 (m)
and 156.0 (M ) [CO (Z)]; 169.7 (m), 170.1 (M ), 171.7 (m)
and 171.8 (M ) [2C, CO]. Compound 15c: Rf 0.15 (PE/AcOEt
1:1, A and C). [a]D20 ꢀ13.1 (c 1.04). IR: nmax 3437, 3005,
1712, 1672, 1497, 1424, 1246, 1191, 1096, and 1002. GCe
MS (usual method but with final temp¼290 ꢁC): tR 12.16;
m/z 445 (Mþꢀ108, 0.36), 390 (7.5), 389 (28), 388 (100),
214 (16), 203 (18), 198 (7.6), 179 (10), 174 (9.7), 156 (19),
91 (58), 82 (8.4), 75 (11), 73 (16), 70 (7.2), 68 (6.0), 56
(5.4), 55 (6.3). 1H NMR (300 MHz, DMSO-d6, rt: 56:44
mixture of rotamers, remains even at 90 ꢁC) at 90 ꢁC: 0.04,
0.05, and 0.07 [6H, 3s, Si(CH3)2]; 0.90 [9H, 2s, SiC(CH3)3];
1.72e2.70 [6H, m, CH2 pyrrolidine, NCOCH2]; 3.21e3.57
(m), 3.62 and 3.74 (AB part of an ABX system, JAB¼9.2,
JAX¼6.1, JBX¼2.7), and 4.06e4.40 (m) [8H, CH2NHZ, CH,
CH2OSi, NHCH2Ph]; 5.04 and 5.04 [2H, AB system,
OCH2Ph, J¼13.0]; 6.65 (M ) [1H, br s, NHZ]; 6.77 (m) [1H,
br s, NHZ]; 7.22e7.39 [10H, m, aromatics]; 8.02 (m) [1H,
br s, NHCH2Ph (at rt: br t at 8.34, J¼5.8)]; 8.30 (M ) [1H, br
6:4, C). GCeMS: unsuitable for this analysis. Selected H
NMR data at 120 ꢁC (300 MHz, DMSO-d6): 0.05, 0.06, 0.07,
and 0.08 [6H, 4s, Si(CH3)2]; 0.90 and 0.91 [9H, 2s, SiC(CH3)3];
1.39 and 1.40 [9H, 2s, OC(CH3)3]; 5.04 and 5.06 [2H, 2s,
OCH2Ph]; 6.25, 6.31, and 6.66 [3H, 3br s, NHZ, NHBoc];
7.70, 7.86, and 8.22 [3H, br s, NHCH2Ph (at rt: 4br t at 7.97,
J¼5.8; 8.25, J¼5.8; 8.46, J¼5.4, and 8.66, J¼5.7)]. Selected
13C NMR data (75 MHz): ꢀ5.5 [2C, Si(CH3)2]; 17.76 and
17.84 [C(CH3)3]; 25.7 [3C, SiC(CH3)3]; 28.0 [3C, OC(CH3)3];
65.3 [CH2O]; 78.2, 78.4, 78.6 [OC(CH3)3]; 155.1, 155.3,
155.5, 155.6, 155.8, 156.0, 156.1, and 156.2 [CO (Z, Boc)];
169.4, 170.0, 171.3, and 171.9 [2C, CO].
4.10.5. Compounds 14 and 15e
i
Chromatography with CH2Cl2/AcOEt 8:2þ1% PrOH/
i
6:4þ1% PrOH gave 14e and 15e both as colorless oils in
66% overall yield. dr: 63:37 (by weight). Compound 14e: Rf
i
0.58 (CH2Cl2/AcOEt 8:2þ1% PrOH, A and C). [a]2D0 þ12.3
(c 1.09). IR: nmax 3428, 2953, 2928, 1738, 1702, 1643,
1439, 1368, 1278, and 1106. GCeMS: unsuitable for this anal-
1
ysis. Selected H NMR data (300 MHz, DMSO-d6, rt: z3:1
mixture of rotamers) at 90 ꢁC: 0.03 and 0.04 [6H, 2s,
Si(CH3)2]; 0.88 [9H, s, SiC(CH3)3]; 1.20 and 1.21 [6H, 2s,
C(CH3)2]; 1.39 [9H, s, OC(CH3)3]; 3.71 [3H, s, OCH3]; 5.07
and 5.06 [2H, AB system, OCH2Ph, J¼13.2]. 13C NMR
(75 MHz): ꢀ5.6 and ꢀ5.5 [2C, Si(CH3)2]; 17.8 [C(CH3)3];
22.7 and 23.9 (M ), 23.6 and 23.8 (m) [2C, C(CH3)2]; 24.5
(M ), 26.4 (m), 27.2 (m), and 30.6 (M ) [2C, CH2 pyrrolidine];
25.7 [3C, SiC(CH3)3]; 28.0 [3C, OC(CH3)3]; 35.0 (M ) and
36.2 (m) [CH2CO2Bn]; 48.1 (m) and 48.6 (M ) [CHNHBoc];
51.9 (m) and 52.2 (M ) [C(CH3)2]; 54.5 [OCH3]; 58.1 (m),
59.3 (M ), 60.2 (m) and 60.3 (M ) [2C, CH pyrrolidine]; 61.8
(M ), 63.6 (m), and 65.4 [2C, CH2]; 70.9 (M ) and 71.0 (m)
[CH2OCO2Me]; 78.0 (M ) and 78.5 (m) [OC(CH3)3]; 127.6,
127.8, 127.9, and 128.2 [5C, CH of Ph]; 135.88 (m) and
135.93 (M ) [C of Ph]; 155.0 [2C, CO (carbonate, Boc)];
169.9 (m), 170.1 (M ), 170.5 (m), 170.8 (M ), 171.1 (m), and
171.8 (M ) [3C, CO]. Compound 15e: Rf 0.33 (CH2Cl2/AcOEt

1124
L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
t
8:2þ1% iPrOH, A and C). [a]D20 ꢀ37.1 (c 2.76). IR: nmax 3426,
1
and 972. GCeMS: unsuitable for this analysis. Selected H
OC(CH3)3]; 37.4 [CH2CO2 Bu]; 48.6 (M ) and 49.6 (m)
2952, 2927, 1742, 1660, 1491, 1440, 1368, 1272, 1158, 1092,
[CHNHZ]; 51.9 (M ) and 52.2 (m) [C(CH3)2]; 54.5 [OCH3];
58.8 (M ), 59.7 (m), 60.2 (M ), and 60.7 (m) [2C, CH pyrroli-
dine]; 62.9 (M ), 63.5 (m), 65.5 [2C, CH2]; 70.9
[CH2OCO2Me]; 80.1 (m) and 80.2 (M ) [OC(CH3)3]; 127.6,
127.8, 128.16, and 128.24 [5C, CH of Ph]; 136.8 [C of Ph];
155.00, 155.4 (m) and 155.6 (M ) [2C, CO (carbonate, Z)];
169.0, 169.2, 169.7, 170.6, and 171.0 [3C, CO].
NMR data (300 MHz, DMSO-d6, rt: z3:1 mixture of ro-
tamers) at 90 ꢁC: 0.06 [6H, s, Si(CH3)2]; 0.89 [9H, s,
SiC(CH3)3]; 1.25 and 1.26 [6H, 2s, C(CH3)2]; 1.39 [9H, s,
OC(CH3)3]; 3.71 [3H, s, OCH3]; 5.10 [2H, s, OCH2Ph]. 13C
NMR (75 MHz): ꢀ5.7, ꢀ5.6, and ꢀ5.4 [2C, Si(CH3)2]; 17.9
[C(CH3)3]; 23.3 (m), 23.4, and 23.6 (M ) [2C, C(CH3)2];
25.7 [3C, SiC(CH3)3]; 26.1 (M ), 26.7 (M ), and 28.9 (m)
[2C, CH2 pyrrolidine]; 28.0 [3C, OC(CH3)3]; 35.7 (m) and
36.2 (M ) [CH2CO2Bn]; 48.1 (M ) and 49.4 (m) [CHNHBoc];
51.9 (M ) and 52.4 (m) [C(CH3)2]; 54.5 (M ) and 54.8 (m)
[OCH3]; 58.9 (M ), 59.7 (m), 60.3 (M ), and 61.0 (m) [2C,
CH pyrrolidine]; 62.8 (M ), 64.0 (m), and 65.5 [2C, CH2];
71.0 [CH2OCO2Me]; 78.4 (M ) and 78.5 (m) [OC(CH3)3];
127.7, 127.9, 128.3, and 128.6 [5C, CH of Ph]; 135.8 [C of
Ph]; 155.0 [2C, CO (carbonate, Boc)]; 169.7 (M ), 169.9 (m),
170.1 (M ), 170.3 (m), 170.5 (m), and 170.9 (M ) [3C, CO].
4.10.7. Compounds 14 and 15g
Chromatography with PE/AcOEt 85:15þ1% EtOH/
75:25þ1% EtOH gave 14 and 15g as an unseparable mixture
(yellow oil) in 47% overall yield. dr: 65:35 [HPLC: column
Hypersil Silica 200ꢂ4.6 mm, 5 mm, hexane/iPrOH 9:1,
flow¼1 ml/min, DAD 230, tR 3.39 (14g) and 5.53 (15g)
min]. Compounds 14 and 15g: Rf 0.30 (PE/AcOEt 7:3, A
1
and C). GCeMS: unsuitable for this analysis. Selected H
NMR data at 90 ꢁC (300 MHz, DMSO-d6): 0.037, 0.044,
0.087, and 0.094 [12H, 4s, Si(CH3)2]; 0.87, 0.90, and 0.93
[18H, 3s, SiC(CH3)3]; 5.01 and 5.03 [2H, 2s, OCH2Ph]; 6.76
[1H, br s, NHZ]; 9.09, 9.15, and 9.29 [1H, 3br s, NHAr (at
rt: 4br s at 9.39, 9.41, 9.50, and 9.58]. 13C NMR (75 MHz):
ꢀ5.4 [4C, Si(CH3)2]; 17.8, 17.85, 18.92, 17.95, and 18.0
[2C, C(CH3)3]; 25.1, 26.2, 26.8, 26.9, 27.5, 29.8, and 30.2
[2C, CH pyrrolidine]; 25.7 [6C, SiC(CH3)3]; 33.6, 33.7,
33.9, 34.1, 36.5, 36.7, and 36.9 [2C, (CH2)2NHZ]; 58.9,
59.1, 59.3, 59.4, 60.4, 60.5, and 60.8 [2C, CH pyrrolidine];
60.9, 61.0, 61.9, 62.4, 63.3, 64.2, and 65.1 [3C, CH2O];
124.4, 125.1, 125.2, 125.4, 125.5, 125.6, 125.9, 126.0, 126.2,
126.3, 126.7, 126.95, 127.01, 127.7, and 128.3 [9C, aromatic
CH]; 133.5, 133.9, 134.0, 134.1, 135.1, 135.3, 135.6, 135.9,
137.0, and 137.1 [3C, aromatic C]; 155.9 [CO (Z)]; 169.7,
170.0, 170.1, 170.3, 170.5, 170.7, and 170.8 [2C, CO].
4.10.6. Compounds 14 and 15f
Chromatography with PE/AcOEt 7:3/2:8 gave 14f as
white foam and 15f as pale yellow oil in 67% overall yield.
dr: 60:40 (by weight). Compound 14f: Rf 0.41 (PE/AcOEt
6:4, A and C). [a]D20 þ17.8 (c 2.16). IR: nmax 3424, 2949,
2928, 1724, 1647, 1436, 1368, 1246, 1156, 1107, 1044, and
834. GCeMS: unsuitable for this analysis. Selected 1H
NMR data (300 MHz, DMSO-d6, rt: 80:20 mixture of ro-
tamers) at 90 ꢁC: ꢀ0.02, 0.01, 0.02, and 0.08 [6H, 4s,
Si(CH3)2]; 0.88 [9H, s, SiC(CH3)3]; 1.25 and 1.30 [6H, 2s,
C(CH3)2]; 1.36 [9H, s, OC(CH3)3]; 3.72 [3H, s, OCH3]; 5.02
and 5.06 [2H, AB system, OCH2Ph, J¼12.0]. 13C NMR
(75 MHz): ꢀ5.64 and ꢀ5.59 [2C, Si(CH3)2]; 17.8 (M ) and
17.9 (m) [C(CH3)3]; 22.8 and 24.13 (M ), 23.6 and 23.8 (m)
[2C, C(CH3)2]; 24.7 (M ), 26.6 (m), 28.9 (m), and 30.6 (M )
[2C, CH2 pyrrolidine]; 25.7 [3C, SiC(CH3)3]; 27.5 [3C,
4.10.8. Compounds 14 and 15h
Chromatography with PE/AcOEt 1:1/3:7 gave 14h and
15h both as orange foams in 75% overall yield. dr: 64:36
[HPLC: column Supelco LC18 250ꢂ4.6 mm, 5 mm, H2O/
MeCN 4:6, flow¼1.2 ml/min, DAD 254, tR 11.91 (14h) and
13.21 (15h) min]. Compound 14h: Rf 0.34 (PE/AcOEt 1:1,
A, B, and C). [a]D20 þ13.9 (c 0.96). IR: nmax 3453, 3018,
1709, 1507, 1412, 1213, 1110, and 725. GCeMS: unsuitable
t
OC(CH3)3]; 36.4 (M ) and 37.3 (m) [CH2CO2 Bu]; 48.5 (m)
and 49.1 (M ) [CHNHZ]; 51.9 (m) and 52.3 (M ) [C(CH3)2];
54.5 [OCH3]; 58.3 (m), 59.2 (M ), 60.2 (m), and 60.6 (M )
[2C, CH pyrrolidine]; 62.1 (M ), 64.2 (m), 65.2 (M ) and
65.4 (m) [2C, CH2]; 70.9 (M ) and 71.0 (m) [CH2OCO2Me];
79.7 (M ) and 80.1 (m) [OC(CH3)3]; 127.3, 127.6, 127.7, and
128.2 [5C, CH of Ph]; 136.9 [C of Ph]; 155.00 (M ) and
155.05 (m), 155.5 (M ) and 155.7 (m) [2C, CO (carbonate,
Z)]; 168.9 (m), 169.1 (M ), 169.3 (m), 170.5 (M ), 171.1 (m),
and 171.8 (M ) [3C, CO]. Compound 15f: Rf 0.30 (PE/AcOEt
6:4, A and C). [a]D20 ꢀ47.1 (c 2.03). IR: nmax 3422, 2952,
2927, 1719, 1637, 1438, 1368, 1259, 1151, 1090, and 719.
GCeMS: unsuitable for this analysis. Selected 1H NMR
data (300 MHz, DMSO-d6, rt: z3:1 mixture of rotamers) at
90 ꢁC: 0.08 [6H, s, Si(CH3)2]; 0.90 [9H, s, SiC(CH3)3]; 1.25
and 1.26 [6H, 2s, C(CH3)2]; 1.40 [9H, s, OC(CH3)3]; 3.72
[3H, s, OCH3]; 5.05 and 5.05 [2H, AB system, OCH2Ph,
J¼13.2]. 13C NMR (75 MHz): ꢀ5.6, ꢀ5.5, and ꢀ5.4 [2C,
Si(CH3)2]; 17.8 (m) and 17.9 (M ) [C(CH3)3]; 23.5 and 23.7
[2C, C(CH3)2]; 25.7 [3C, SiC(CH3)3]; 26.3 (M ), 26.6 (M ),
28.9 (m), and 30.1 (m) [2C, CH2 pyrrolidine]; 27.5 [3C,
1
for this analysis. H NMR (300 MHz, DMSO-d6, rt: 51:49
mixture of rotamers, remains even at 90 ꢁC) at 90 ꢁC: 0.05,
0.06, and 0.08 [6H, 3s, Si(CH3)2]; 0.91 [9H, s, SiC(CH3)3];
1.83e2.72 [6H, m, CH2 pyrrolidine, NCOCH2]; 3.28 [2H,
center of m, CH2NHZ]; 3.56e3.79 [2H, m, CHCH2OSi];
3.74 [3H, s, OCH3]; 4.11 and 4.18 [1H, centers of 2m,
CHCH2OSi]; 4.43 and 4.49 [1H, 2d, CHCONH, J¼8.7
both]; 5.00 and 5.05 [2H, 2s, OCH2Ph]; 6.68 and 6.75 [1H,
2br s, NHZ, (at rt: 2br t at 7.14 and 7.18, J¼6.0, 5.7)]; 6.85
and 6.88 [2H, 2d, CH meta to OMe, J¼8.4, 8.1]; 7.27e7.37
[5H, m, aromatics]; 7.46 [2H, d, CH ortho to OMe, J¼8.4];
9.46 and 9.70 [1H, br s, NH-pAn (at rt: 2s at 9.79 and
10.01)]. 13C NMR (75 MHz): ꢀ5.6, ꢀ5.52, and ꢀ5.46 [2C,
Si(CH3)2]; 17.78 and 17.83 [C(CH3)3]; 25.1, 26.8, 27.5, and
30.1 [2C, CH2 pyrrolidine]; 25.7 [3C, SiC(CH3)3]; 33.9 and

L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
1125
34.0 [NCOCH2]; 36.4 and 36.9 [CH2NHZ]; 55.1 [OCH3]; 58.9
4.11. General procedure for TBDMS removal on
compounds 14 and 15
and 59.1 [CHCH2OSi]; 60.5 and 60.8 [CHCONH]; 62.1 and
64.4 [CH2OSi]; 65.05 and 65.11 [OCH2Ph]; 113.6 and 113.8
[2C, CH ortho to OMe]; 120.5 and 121.0 [2C, CH meta to
OMe]; 127.6, 127.7, 128.21, and 128.24 [5C, CH of Ph];
131.7 and 132.3 [C-NH]; 137.0 and 137.1 [C of Ph]; 155.0,
155.4, 155.8, and 155.9 [2C, C-OMe, CO (Z)]; 169.6, 169.7,
170.0, and 170.2 [2C, CO]. Compound 15h: Rf 0.23 (PE/
AcOEt 1:1, A, B, and C). [a]2D0 ꢀ60.1 (c 1.00). IR: nmax
3440, 2951, 1709, 1598, 1502, 1416, 1192, 1087, and 830.
A solution of the substrate, either 14 or 15 or a mixture of
both (for preparative purposes), in MeCN was cooled to 0 ꢁC
and treated with 40% HF (1:20 ratio HF/MeCN) was reached.
After stirring at 0 ꢁC for 2e4 h, the reaction was quenched
with 5% NaHCO3 saturated with NaCl and extracted with
AcOEt. After drying, the solvent was evaporated and the crude
directly chromatographed with the appropriate PE/AcOEt
mixture.
1
GCeMS: unsuitable for this analysis. H NMR (300 MHz,
DMSO-d6, rt: 68:32 mixture of rotamers) at 90 ꢁC: 0.066
and 0.069 [6H, 3s, Si(CH3)2]; 0.89 [9H, s, SiC(CH3)3];
1.89e2.65 [6H, m, CH2 pyrrolidine, NCOCH2]; 3.29 [2H, br
q, CH2NHZ, J¼6.5]; 3.56e3.90 [2H, m, CHCH2OSi]; 3.75
[3H, s, OCH3]; 4.09 [1H, br s, CHCH2OSi]; 4.48 [1H, t,
CHCONH, J¼7.5]; 5.03 [2H, s, OCH2Ph]; 6.77 [1H, br s,
NHZ (at rt: 2br t at 7.16 (m) and 7.22 (M ), J¼5.7 both)];
6.87 [2H, dt, CH meta to OMe, J¼9.0, 2.8]; 7.28e7.38 [5H,
m, aromatics]; 7.45 [2H, dt, CH ortho to OMe, J¼9.0, 2.7];
9.50 [1H, br s, NH-pAn (at rt: 2s at 9.84 (M ) and 9.94 (m)].
13C NMR (75 MHz): ꢀ5.6, ꢀ5.4, and ꢀ5.3 [2C, Si(CH3)2];
17.8 (M ) and 17.9 (m) [C(CH3)3]; 25.7 [3C, SiC(CH3)3];
25.9, 26.9, and 29.8 [2C, CH2 pyrrolidine]; 33.4 [NCOCH2];
36.3 (m) and 36.7 (M ) [CH2NHZ]; 55.0 [OCH3]; 59.2 (m)
and 59.4 (M ) [CHCH2OSi]; 60.6 [CHCONH]; 62.1 (m) and
63.3 (M ) [CH2OSi]; 65.1 [OCH2Ph]; 113.66 (M ) and 113.74
(m) [2C, CH ortho to OMe]; 120.4 (M ) and 121.3 (m) [2C,
CH meta to OMe]; 127.6, 127.7, 128.21, and 128.24 [5C,
CH of Ph]; 131.5 (m) and 132.2 (M ) [C-NH]; 137.0 (m) and
137.1 (M ) [C of Ph]; 155.0 (M ), 155.5 (m), and 155.9 [2C,
C-OMe, CO (Z)]; 169.5, 169.7, and 170.0 [2C, CO].
4.11.1. Compounds 16 and 17
Chromatography with CH2Cl2/AcOEt 4:6þ1% MeOH/
2:8þ2% MeOH gave 16 and 17 both as white foams in 94%
overall yield. Compound 16: Rf 0.21 (CH2Cl2/AcOEt 4:6þ1%
MeOH, A and C). Anal. Found: C, 64.70; H, 6.80; N, 7.90.
C29H37N3O7 requires C, 64.55; H, 6.91; N, 7.79. [a]2D0 þ6.9
(c 2.08) and þ28.8 (c 2.08, EtOH). IR: nmax 3423, 3004,
1690, 1643, 1491, 1434, 1245, 1155, and 1041. GCeMS: un-
1
suitable for this analysis. H NMR (200 MHz, DMSO-d6, rt:
66:34 mixture of rotamers) at 100 ꢁC: 1.38 [9H, s,
OC(CH3)3]; 1.62e4.78 [13H, m, CH2 pyrrolidine, CH2CO2Bn,
CH2Ph, CH2OH, 3CH]; 5.10 [2H, s, OCH2Ph]; 6.77 [1H, br s,
NHBoc]; 7.21e7.36 [10H, m, aromatics]; 7.74 [1H, br s,
NHCH2Ph (at rt: br s at 7.99 (m))]; 8.34 [1H, br s, NHCH2Ph
(at rt: br s at 8.69 (M ))]. 13C NMR (50 MHz): 24.5 (M ), 26.6
(m), 27.2 (m), and 29.7 (M ) [2C, CH2 pyrrolidine]; 28.0 [3C,
OC(CH3)3]; 35.0 (M ) and 35.9 (m) [CH2CO2Bn]; 41.7 (m)
and 42.2 (M ) [NHCH2Ph]; 48.5 (m) and 48.9 (M ) [CHNHBoc];
58.8 (m) and 59.8 (M ), 60.0 (M ) and 60.4 (m) [2C, CH pyrro-
lidine]; 62.4 and 65.3 [2C, CH2O]; 78.2 (M ) and 78.6 (m)
[OC(CH3)3]; 126.5, 126.7, 127.1, 127.56, 127.64, 127.8,
128.1, and 128.3 [10C, aromatic CH]; 136.0 (m) and 136.1
(M ), 139.0 (m) and 139.4 (M ) [2C, aromatic C]; 155.1 (M )
and 155.4 (m) [CO (Boc)]; 169.6, 170.0, 170.1, 170.3, 171.4,
and 171.8 [3C, CO]. Compound 17: Rf 0.36 (CH2Cl2/AcOEt
4:6þ1% MeOH, A and C). Anal. Found: C, 64.45; H, 6.85;
N, 7.95. C29H37N3O7 requires C, 64.55; H, 6.91; N, 7.79.
[a]2D0 ꢀ60.7 (c 1.98) and ꢀ46.3 (c 2.06, EtOH). IR: nmax
3427, 2998, 1710, 1658, 1491, 1429, 1296, 1157, and 1053.
4.10.9. Compounds 14 and 15i
Chromatography with CH2Cl2/AcOEt 9:1þ2% MeOH/
8:2þ2% MeOH gave 14i and 15i both as colorless oils in
1
81% overall yield. dr: 68:32 (by H NMR). Compound 14i:
Rf 0.33 (CH2Cl2/AcOEt 9:1þ2% MeOH, A and B). [a]D20
þ100.2 (c 1.80). Compound 15i: Rf 0.44 (CH2Cl2/AcOEt
9:1þ2% MeOH, A and B). [a]2D0 ꢀ31.1 (c 2.04). The follow-
ing spectroscopic data have been taken on the purified diaste-
reomeric mixture. GCeMS: a partial decomposition occurred.
1
1
Selected H NMR data (300 MHz, DMSO-d6, rt: two diaste-
GCeMS: unsuitable for this analysis. H NMR (200 MHz,
reoisomer both as a z1:1 mixture of rotamers): ꢀ0.23 and
ꢀ0.20 (minor diast.), 0.07 and 0.08 (major diast.) [6H, 4s,
Si(CH3)2]; 0.72, 0.90, 0.91, 1.10, 1.24, and 1.25 [15H, 6s,
SiC(CH3)3, C(CH3)2]; 3.67, 3.68, and 3.69 [3H, 3s, OCH3].
13C NMR (75 MHz): ꢀ6.1, ꢀ5.8, and ꢀ5.5 [2C, Si(CH3)2];
17.6 and 17.8 [C(CH3)3]; 22.7 and 22.9, 23.53, and 23.55
[2C, C(CH3)2]; 24.9, 25.1, 26.6, 28.8, 27.5, and 30.7 [2C,
CH2 pyrrolidine]; 25.6 and 25.8 [3C, SiC(CH3)3]; 51.6, 51.9,
and 52.0 [C(CH3)2]; 54.5 and 54.9 [OCH3]; 59.2, 59.6, 59.8,
and 60.2 [2C, CH pyrrolidine]; 62.2, 62.6, 63.1, and 63.3
[2C, CH2]; 70.8, 71.1, and 71.9 [CH2OCO2Me]; 126.3,
126.6, 127.7, 128.0, 128.2, 128.9, and 129.3 [5C, CH of
Ph]; 137.0, 137.4, and 137.6 [5C, CH of Ph]; 154.9 and
155.0 [CO (carbonate)]; 168.8, 170.0, and 171.3 [2C, CO].
DMSO-d6, rt: 77:23 mixture of rotamers) at 100 ꢁC: 1.39
[9H, s, OC(CH3)3]; 1.90e2.20 [4H, m, CH2 pyrrolidine]; 2.66
and 2.82 [2H, AB part of an ABX system, CH2CO2Bn,
JAB¼16.2, JAX¼7.7, JBX¼6.1]; 3.45e4.80 [7H, m, CH2Ph,
CH2OH, 3CH]; 5.07 [2H, s, OCH2Ph]; 6.79 [1H, br s, NHBoc];
7.21e7.35 [10H, m, aromatics]; 8.05 [1H, br s, NHCH2Ph (at rt:
2br s at 8.25 (M ) and 8.55 (m))]. 13C NMR (50 MHz): 25.4 (m),
27.3 (M ), 27.5 (M ), and 29.9 (m) [2C, CH2 pyrrolidine]; 28.0
[3C, OC(CH3)3]; 36.1 (M ) and 36.5 (m) [CH2CO2Bn]; 41.8
(M ) and 42.5 (m) [NHCH2Ph]; 48.2 (M ) and 49.3 (m)
[CHNHBoc]; 59.3, 60.5, and 61.2 [2C, CH pyrrolidine]; 60.8
(m) and 62.5 (M ), 65.4 [2C, CH2O]; 78.3 [OC(CH3)3]; 126.5,
126.7, 127.0, 127.6, 127.8, 128.1, 128.2, and 128.3 [10C, aro-
matic CH]; 135.9, 138.8 (m), and 139.2 (M ) [2C, aromatic

1126
L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
C]; 154.6 (m) and 155.0 (M ) [CO (Boc)]; 169.6, 170.1, 170.3,
170.5, 171.5, and 172.1 [3C, CO].
1:1þ1% EtOH, A and C). Anal. Found: C, 65.70; H, 6.75;
N, 9.35. C24H29N3O5 requires C, 65.59; H, 6.65; N, 9.56.
[a]2D0 þ18.4 (c 1.00, EtOH). Mp: 147.5e148.1 ꢁC (PE/
Me2CO). IR (KBr): nmax 3430, 3325, 3293, 2950, 2885,
1680, 1652, 1633, 1550, 1441, 1283, 1262, and 700. GCe
MS (usual method but with final temp¼290 ꢁC): decomposes
4.11.2. Compounds 18 and 19
Chromatography with CH2Cl2/AcOEt 4:6þ1% MeOH/
AcOEtþ1% MeOH gave 18 and 19 both as white foams in
92% overall yield. Compound 18: Rf 0.30 (CH2Cl2/AcOEt
4:6þ1% MeOH, A and C). Anal. Found: C, 64.60; H, 6.95;
N, 7.70. C29H37N3O7 requires C, 64.55; H, 6.91; N, 7.79.
[a]2D0 þ32.3 (c 3.15) and þ34.9 (c 1.62, EtOH). IR: nmax
3423, 3386, 3017, 1712, 1648, 1423, 1195, and 1046. GCe
MS: unsuitable for this analysis. 1H NMR (300 MHz,
DMSO-d6, rt: 91:9 mixture of rotamers): 1.37 [9H, s,
OC(CH3)3]; 1.58e2.89 (m), 2.59 and 2.85 (M ) (AB part of
an ABX system, JAB¼17.0, JAX¼10.7, JBX¼2.5) [6H, CH2
pyrrolidine, CH2CO2Bn]; 3.82e4.72 (m), 4.21 and 4.29 (M )
(AB part of an ABX system, JAB¼15.6, JAX¼JBX¼7.7),
4.97 (br t, J¼5.1) [7H, m, CH2Ph, CH2OH, 3CH]; 5.10 and
5.10 [2H, AB system, OCH2Ph, J¼13.4]; 7.20e7.38 [11H,
m, aromatics, NHBoc]; 8.24 (M ) [1H, br t, NHCH2Ph,
J¼6.0]; 8.45 (m) [1H, br t, NHCH2Ph, J¼5.9]. 13C NMR
(75 MHz): 24.4 (m), 26.2 (M ), 26.7 (M ), and 28.9 (m) [2C,
CH2 pyrrolidine]; 28.1 [3C, OC(CH3)3]; 35.8 (M ) and 37.6
(m) [CH2CO2Bn]; 41.8 (M ) and 42.4 (m) [NHCH2Ph]; 49.0
(M ) and 49.1 (m) [CHNHBoc]; 59.0 (M ), 59.7 (m), 59.9
(M ), and 60.3 (m) [2C, CH pyrrolidine]; 61.8 and 65.7 [2C,
CH2O]; 78.0 [OC(CH3)3]; 126.5, 126.6, 126.8, 127.0, 127.1,
127.7, 127.8, 127.9, 128.1, 128.2, and 128.3 [10C, aromatic
CH]; 135.9, 139.2 (m), and 139.4 (M ) [2C, aromatic C];
154.2 (m) and 155.1 (M ) [CO (Boc)]; 169.6 (m), 169.7 (m),
170.0 (M ), 170.2 (M ), 171.1 (m), and 171.5 (M ) [3C, CO].
Compound 19: Rf 0.44 (CH2Cl2/AcOEt 4:6þ1% MeOH,
A and C). Anal. Found: C, 64.40; H, 7.00; N, 7.80.
C29H37N3O7 requires C, 64.55; H, 6.91; N, 7.79. [a]2D0 ꢀ1.5
(c 1.67) and ꢀ3.4 (c 1.30, EtOH). IR: nmax 3428, 2975,
1703, 1658, 1494, 1426, 1369, 1190, and 1080. GCeMS: un-
1
in the column. H NMR (300 MHz, DMSO-d6, rt: 53:47 mix-
ture of rotamers, remains even at 90 ꢁC): 1.66e2.67 [6H, m,
CH2 pyrrolidine, NCOCH2]; 3.16e4.37 [6H, m, CH2NHZ,
NHCH2Ph, CH2OH]; 4.00 and 4.07 [1H, centers of 2m,
CHCH2OH]; 4.68 and 4.96 [1H, 2br t, CHCO, J¼5.7, 5.6];
5.01 [2H, s, OCH2Ph]; 7.13e7.40 [11H, m, aromatics, NHZ
(at 90 ꢁC: 2br s at 6.66 and 6.74)]; 8.29 and 8.59 [1H, 2br t,
NHCH2Ph, J¼5.8 both (at 90 ꢁC: 2br s at 7.98 and 8.28)].
13C NMR (75 MHz): 25.1, 26.6, 27.4, and 29.9 [2C, CH2 pyr-
rolidine]; 33.9 and 34.2 [NCOCH2]; 36.5 and 37.1 [CH2NHZ];
41.8 and 42.2 [NHCH2Ph]; 59.4, 59.6, 60.2, and 60.5 [2C, CH
pyrrolidine]; 60.6 and 62.5 [CH2OH]; 65.2 [OCH2Ph]; 126.6,
126.8, 127.1, 127.7, 128.2, and 128.3 [10C, aromatic CH];
137.1, 139.3, and 139.6 [2C, aromatic C]; 155.95 and 156.00
[CO (Z)]; 169.7, 169.8, 171.9, and 172.1 [2C, CO]. Compound
31: Rf 0.37 (PE/Me2CO 1:1þ1% EtOH, A and C). Anal.
Found: C, 65.50; H, 6.70; N, 9.45. C24H29N3O5 requires C,
65.59; H, 6.65; N, 9.56. [a]2D0 ꢀ7.6 (c 1.00, EtOH). IR: nmax
3433, 2950, 1707, 1641, 1501, 1413, 1247, and 1071. GCe
MS (usual method but with final temp¼290 ꢁC): decomposes
1
in the column. H NMR (300 MHz, DMSO-d6, rt: 56:44 mix-
ture of rotamers, remains even at 90 ꢁC): 1.80e2.68 [6H, m,
CH2 pyrrolidine, NCOCH2]; 3.20e5.00 [10H, m, CH2NHZ
(at 90 ꢁC: br q at 3.28, J¼6.3), NHCH2Ph, CH2OH, CH,
OCH2Ph]; 7.20e7.36 [11H, m, aromatics, NHZ (at 90 ꢁC:
br s at 6.74)]; 8.40 and 8.70 [1H, 2br s, NHCH2Ph (at 90 ꢁC:
2br s at 8.11 and 8.47)]. 13C NMR (75 MHz): 25.8, 27.5,
27.7, and 29.9 [2C, CH2 pyrrolidine]; 33.6 and 34.1
[NCOCH2]; 36.4 and 36.8 [CH2NHZ]; 41.9 and 42.2
[NHCH2Ph]; 59.7, 59.9, 60.3, and 61.1 [2C, CH pyrrolidine];
60.6 and 62.6 [CH2OH]; 65.2 [OCH2Ph]; 126.6, 126.8,
127.0, 127.8, 128.2, and 128.4 [10C, aromatic CH]; 137.1,
139.0, and 139.3 [2C, aromatic C]; 155.99 and 156.04 [CO
(Z)]; 170.0, 170.3, 172.5, and 172.7 [2C, CO].
1
suitable for this analysis. H NMR (300 MHz, DMSO-d6, rt:
two major rotamers in a 49:51 ratio) at 100 ꢁC: 1.38 [9H, s,
OC(CH3)3]; 1.80e3.00 [6H, m, CH2 pyrrolidine, CH2CO2Bn];
3.50e4.90 (m), 4.10 (quintuplet, J¼5.4) [7H, CH2Ph, CH2OH,
3CH]; 5.09 [2H, s, OCH2Ph]; 6.78 [1H, br s, NHBoc]; 7.19e
7.40 [10H, m, aromatics]; 8.02 [1H, br s, NHCH2Ph (at rt: br t
at 8.26, J¼6.0)]; 8.52 [1H, br s, NHCH2Ph (at rt: br t at 8.83,
J¼5.6)]. 13C NMR (75 MHz): 25.5, 27.1, 28.9, and 30.1 [2C,
CH2 pyrrolidine]; 28.02 and 28.06 [3C, OC(CH3)3]; 35.4 and
36.5 [CH2CO2Bn]; 41.8 and 42.2 [NHCH2Ph]; 48.5 and 48.7
[CHNHBoc]; 59.7, 59.8, 60.4, and 60.6 [2C, CH pyrrolidine];
60.2 and 61.9, 65.4 and 65.6 [2C, CH2O]; 78.2 and 78.4
[OC(CH3)3]; 126.6, 126.7, 127.0, 127.6, 127.7, 127.8, 127.9,
128.1, 128.2, and 128.3 [10C, aromatic CH]; 135.9 and
136.0, 138.7 and 139.1 [2C, aromatic C]; 154.9 and 155.2
[CO (Boc)]; 169.7, 169.9, 170.8, and 172.1 [3C, CO].
4.11.4. Compounds 36 and 37
Chromatography with PE/Me2CO 1:1/3:7 gave 36 and 37
both as white foam in 98% overall yield. Compound 36: Rf 0.18
(PE/Me2CO 1:1, A and C). Anal. Found: C, 62.75; H, 6.85; N,
10.15. C29H38N4O7 requires C, 62.80; H, 6.91; N, 10.10. [a]D20
þ1.8 (c 0.94). IR: nmax 3429, 2998, 1693, 1499, 1418, 1230,
1155, and 1087. GCeMS: unsuitable for this analysis. 1H
NMR (300 MHz, DMSO-d6, rt: four rotamers can be detected
with the two highly prevailing (z90%) in a 53:47 ratio) at
120 ꢁC (two rotamers): 1.39 [9H, s C(CH3)3]; 1.64e4.75
[13H, m, CH2 pyrrolidine, NHCH2Ph, CH2OH, CH2NHZ,
CH]; 5.06 [2H, s, OCH2Ph]; 6.31 and 6.57 [2H, 2br s, NHZ,
NHBoc (at rt: br s at 6.81 (NHBoc, one rotamer), 2d at 6.90
and 6.99 (NHZ), J¼7.5, 6.3)]; 7.19e7.37 [10H, m, aromatics];
7.62 and 8.18 [1H, 2br s, NHCH2Ph (at rt: 2br t at 7.88 and 8.62,
J¼5.8, 5.4)]. 13C NMR (75 MHz) (only the signals of the two
4.11.3. Compounds 30 and 31
Chromatography with PE/Me2CO 1:1þ1% EtOH/
Me2COþ2% EtOH gave 30 as a white solid and 31 as a yellow
oil in 89% overall yield. Compound 30: Rf 0.18 (PE/Me2CO

L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
1127
highly prevailing rotamers have been reported): 24.5, 26.7, 27.3,
and 29.8 [2C, CH2 pyrrolidine]; 27.9 and 28.0 [3C, OC(CH3)3];
40.8, 41.7, 41.9, and 42.5 [2C, CH2N]; 51.4 [CHNHBoc]; 59.0,
59.7, 60.1, and 60.8 [2C, CH pyrrolidine]; 62.6, 65.3, and 65.4
[2C, CH2O]; 78.4 and 78.7 [OC(CH3)3]; 126.5, 126.7, 127.2,
127.6, 127.7, 128.1, 128.21, 128.24, and 128.3 [10C, aromatic
CH]; 136.9, 137.0, 139.2, and 139.3 [2C, aromatic C]; 155.3,
155.7, 156.0, and 156.2 [2C, CO (Z and Boc)]; 169.6, 169.9,
171.3, and 171.8 [2C, CO]. Compound 37: Rf 0.39 (PE/
Me2CO 1:1, A and C). Anal. Found: C, 62.95; H, 6.80; N,
10.25. C29H38N4O7 requires C, 62.80; H, 6.91; N, 10.10. [a]D20
ꢀ21.1 (c 1.00, EtOH). IR: nmax 3437, 3026, 1703, 1644, 1491,
1252, 1155, and 1038. GCeMS: unsuitable for this analysis.
1H NMR (300 MHz, DMSO-d6, rt: four rotamers can be de-
tected with the two highly prevailing (z80%) in a z2:1 ratio)
at 120 ꢁC: 1.40 [9H, s C(CH3)3]; 1.85e2.18 [4H, CH2 pyrroli-
dine]; 3.23e3.42 (m), 3.57 and 3.65 (AB part of an ABX sys-
tem, JAB¼11.1, JAX¼4.7, JBX¼6.1), 4.25e5.06 [9H,
NHCH2Ph, CH2OH, CH2NHZ, CH]; 5.05 [2H, s, OCH2Ph];
6.24 and 6.64 [2H, 2br s, NHZ, NHBoc]; 7.19e7.37 [10H, m,
aromatics]; 8.02 [1H, br s, NHCH2Ph (at rt: 2br t at 8.36 and
8.58, J¼5.7, 5.8)]. 13C NMR (75 MHz) (this spectrum is very
complex, due to the presence of four rotamers; only the highly
prevailing signals have been reported): 26.0, 27.3, 27.6, and
28.3 [2C, CH2 pyrrolidine]; 28.0 [3C, OC(CH3)3]; 41.8 [2C,
CH2N]; 51.3 [CHNHBoc]; 59.4, 60.4, and 61.4 [2C, CH pyrro-
lidine]; 62.4 and 65.3 [2C, CH2O]; 78.3 and 78.5 [OC(CH3)3];
126.6, 126.7, 126.9, 127.1, 127.5, 127.6, 127.7, 128.1, 128.2,
and 128.3 [10C, aromatic CH]; 136.9, 138.8, and 139.2 [2C,
aromatic C]; 155.3, and 156.2 [2C, CO (Z and Boc)]; 170.2
and 172.1 [2C, CO].
CHCH2OH, J¼5.4]; 4.47e4.58 [2H, m, ArCH2OH]; 4.77
[1H, center of m, CHCONH]; 5.04 [2H, s, OCH2Ph]; 6.79
[1H, br s, NHZ]; 7.13 [1H, t, CH para to NH, J¼7.4];
7.23 [1H, dt, CH para to CH2OH, J¼7.6, 1.8]; 7.28e7.39
[6H, m, aromatics]; 7.64 [1H, d, CH ortho to NH, J¼7.8];
9.35 [1H, br s, NHAr (at rt: 2s at 9.43 and 9.80)]. 13C NMR
(75 MHz): 26.0, 27.4, and 29.9 [2C, CH pyrrolidine]; 33.6
(M ) and 34.0 (m) [NCOCH2]; 36.4 (m) and 36.7 (M )
[CH2NHZ]; 59.9 (M ) and 60.0 (m), 61.3 (M ) and 61.8 (m)
[2C, CH pyrrolidine]; 59.9, 60.6, 61.8, 62.2, and 65.2 [3C,
CH2O]; 122.9, 124.3, 125.2, 127.0, 127.2, 127.4, 127.7, and
128.3 [9C, aromatic CH]; 133.7 (M ) and 134.6 (m), 135.2
(m) and 135.6 (M ), and 137.1 [3C, aromatic C]; 156.0 [CO
(Z)]; 170.7, 170.8, and 171.1 [2C, CO].
4.12. General procedure for eight-membered lactone
formation
(a) Benzyl ether removal: to a solution of 16, 17, 18, or 19
(193 mg, 357.7 mmol) in EtOH (5 ml) Pd/C (19 mg) was
added and the mixture was hydrogenated for 1 h. The catalyst
was filtered and the solvent was removed. The crude hydroxy
acid was dissolved in dry CH2Cl2 and dry toluene was added
trice and evaporated to furnish a white solid. (b) Cyclization:
a solution of the previously obtained hydroxy acid in dry
CH2Cl2 (179 ml, 2 mM) was cooled to 0 ꢁC and treated with
Et3N (150 ml, 1.07 mmol) and PyBOP (279 mg, 536.6 mmol).
After 10 min the solution was refluxed for 40e45 h (acid
from 16 and 18) or 19e29 h (acid from 17 and 19). This solu-
tion was washed with 5% NaHCO3, dried, and concentrated
under reduce pressure.
4.11.5. Compounds 50 and 51
4.12.1. (5S,8R,10aR)-N-Benzyl-5-[(tert-butoxycarbonyl)-
amino]-octahydro-3,6-dioxo-1H-pyrrolo[2,1-c][1,4]-
oxazocine-8-carboxamide 20
Chromatography with PE/Me2CO 4:6/4:6þ2% EtOH
gave 50 and 51 both as white foams in 77% overall yield (un-
optimized). Both have been only partially characterized only
in order to identify them. Compound 50: Rf 0.22 (PE/
Chromatography with CH2Cl2/AcOEt 4:6 gave 20 as a pale
yellow solid in 86% yield. Rf 0.38 (CH2Cl2/AcOEt 4:6, A, C,
and D). Anal. Found: C, 61.35; H, 6.80; N, 9.65. C22H29N3O6
requires C, 61.24; H, 6.77; N, 9.74. [a]2D0 ꢀ8.8 (c 1.92, EtOH).
Mp: 127.3e129.0 ꢁC (CH2Cl2/AcOEt). IR: nmax 3430, 3002,
1758, 1694, 1641, 1158, 1130, and 828. GCeMS: unsuitable
1
Me2CO 4:6, A and C). Selected H NMR data at 90 ꢁC
(300 MHz, DMSO-d6, 61:39 mixture of rotamers even at
90 ꢁC): 4.54 [2H, s, ArCH2OH]; 5.01 and 5.04 [2H, 2s,
OCH2Ph]; 6.74 [1H, br s, NHZ]; 7.10 and 7.13 [1H, 2 t, CH
para to NH, J¼7.1, 6.6]; 7.17e7.38 [7H, m, aromatics];
7.60 and 7.63 [1H, 2d, CH ortho to NH, J¼8.7, 8.1]; 9.25
(M ) and 9.43 (m) [1H, 2s, NHAr (at rt: 2s at 9.45 and 9.63].
13C NMR (75 MHz): 25.0 (m), 26.7 (M ), 27.2 (M ), and
30.0 (m) [2C, CH pyrrolidine]; 33.8 (M ) and 34.2 (m)
[NCOCH2]; 36.5 (m) and 36.8 (M ) [CH2NHZ]; 59.4 (M )
and 59.6 (m), 60.8 (M ) and 61.0 (m) [2C, CH pyrrolidine];
60.2, 60.4, 60.6, 62.3, and 65.2 [3C, CH2O]; 123.3, 124.3,
124.5, 125.1, 127.0, 127.2, 127.7, and 128.3 [9C, aromatic
CH]; 134.2 (M ) and 134.9 (m), 135.0 (m) and 135.6 (M ),
and 137.1 [3C, aromatic C]; 156.0 [CO (Z)]; 169.9, 170.6,
and 170.8 [2C, CO]. Compound 51: Rf 0.32 (PE/Me2CO 4:6,
1
for this analysis. H NMR (200 MHz, DMSO-d6, rt: 82:18
mixture of rotamers): 1.37 [9H, s, OC(CH3)3]; 1.69e2.22
[4H, m, CH2 pyrrolidine]; 2.42 and 3.24 (M ) [2H, AB part
of an ABX system, CH2CO, JAB¼13.2, JAX¼11.0, JBX
¼
6.6]; 4.17e4.48 [6H, m, CH2Ph, CH2O, CH pyrrolidine];
4.90 (M ) [1H, dt, CHNHBoc, J¼10.6, 7.4]; 6.77 (m) [1H,
d, NHBoc, J¼7.2]; 6.94 (M ) [1H, d, NHBoc, J¼7.8];
7.18e7.34 [5H, m, aromatics]; 8.25 (M ) [1H, br t, NHCH2Ph,
J¼5.9]; 8.41 (m) [1H, br t, NHCH2Ph, J¼5.7]. 13C NMR
(50 MHz): 26.9 and 27.5 [2C, CH2 pyrrolidine]; 28.1 [3C,
OC(CH3)3]; 41.2 and 41.8 [2C, NHCH2Ph, CH2CO]; 50.3
(M ) and 51.3 [CHNHBoc]; 59.8, 60.7 (m), and 61.1 (M )
[2C, CH pyrrolidine]; 71.8 (M ) and 72.3 (m) [CH2O]; 78.7
[OC(CH3)3]; 126.6 [CH para (Ph)]; 126.8 [2C, CH ortho
(Ph)]; 128.2 [2C, CH meta (Ph)]; 139.3 [C (Ph)]; 154.0 (m)
and 154.6 (M ) [CO (Boc)]; 170.3, 171.1, and 173.2 [3C, CO].
1
A and C). H NMR (300 MHz, DMSO-d6, rt: 67:33 mixture
of rotamers) at 90 ꢁC: 1.93e2.30 [4H, m, CH2 pyrrolidine];
2.61 [2H, center of m, CH2CO]; 3.32 [2H, q, CH2NH,
J¼6.6]; 3.60 [2H, br s, CH2OH]; 4.10 [1H, quintuplet,

1128
L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
4.12.2. Stereoisomer (5S,8S,10aR) 21
completed with CH2Cl2/MeOH 1:1. After drying and solvent
removal, the crude acid was used as such for the following es-
terification. (b) Methyl ester formation: after dissolving the
acid in THF (5 ml) and cooling to 0 ꢁC, CH2N2 was added
dropwise until the yellow color persisted. After addition of
few drops of AcOH the solvent was distilled in vacuo and ex-
cess AcOH was azeotropically removed with heptane. The
crude was directly purified by chromatography.
Chromatography with CH2Cl2/AcOEt 4:6 gave 21 as
a white foam in 90% yield. Rf 0.34 (CH2Cl2/AcOEt 4:6, A,
C, and D). Anal. Found: C, 61.45; H, 6.65; N, 9.55.
C22H29N3O6 requires C, 61.24; H, 6.77; N, 9.74. [a]D20
ꢀ62.6 (c 0.90, EtOH). IR: nmax 3417, 2959, 1745, 1704,
1666, 1255, 1157, and 1011. GCeMS: unsuitable for this anal-
1
ysis. H NMR (300 MHz, DMSO-d6, rt: 86:14 mixture of ro-
tamers): 1.34 (m) and 1.38 (M ) [9H, s, OC(CH3)3]; 1.76e2.18
[4H, m, CH2 pyrrolidine]; 2.60 and 3.05 (M ) [2H, AB part of
an ABX system, CH2CO, JAB¼14.3, JAX¼10.8, JBX¼5.5];
4.21e4.79 [7H, m, CH2Ph, CH2O, CH pyrrolidine,
CHNHBoc]; 6.89 (m) [1H, d, NHBoc, J¼6.6]; 7.18 (M )
[1H, d, NHBoc, J¼7.8]; 7.21e7.35 [5H, m, aromatics]; 8.04
[1H, br t, NHCH2Ph, J¼6.0]. 13C NMR (75 MHz): 27.6 [2C,
CH2 pyrrolidine]; 28.1 [3C, OC(CH3)3]; 39.7 and 41.9 [2C,
NHCH2Ph, CH2CO]; 49.2 (m) and 49.3 (M ) [CHNHBoc];
60.2 and 61.5 [2C, CH pyrrolidine]; 72.2 (M ) and 72.8 (m)
[CH2O]; 78.3 [OC(CH3)3]; 126.6 [CH para (Ph)]; 126.9
[2C, CH ortho (Ph)]; 128.2 [2C, CH meta (Ph)]; 139.1
[C (Ph)]; 154.8 [CO (Boc)]; 170.6, 170.7, and 172.9 [3C, CO].
4.13.1. Compound 32
Chromatography with PE/AcOEt 3:7/15:85 gave 32 as
a white foam in 75% overall yield. Rf 0.41 (PE/AcOEt 1:9,
C). Anal. Found: C, 64.35; H, 6.35; N, 8.90. C25H29N3O6 re-
quires C, 64.23; H, 6.25; N, 8.99. [a]2D0 þ45.4 (c 1.32). IR:
nmax 3429, 3014, 1712, 1675, 1500, 1225, and 1075. GCeMS:
1
unsuitable for this analysis. H NMR (300 MHz, DMSO-d6,
62:38 mixture of rotamers even at 90 ꢁC) at 90 ꢁC: 1.84e2.56
[6H, m, CH2 pyrrolidine, NCOCH2]; 3.20e3.30 [2H, m,
CH2NHZ]; 3.64 (M ) and 3.72 (m) [3H, 2s, OCH3]; 4.28e4.72
[4H, m, CH, NHCH2Ph]; 5.04 (m) and 5.05 (M ) [2H, s,
OCH2Ph]; 6.66 (M ) and 6.72 (m) [1H, br s, NHZ]; 7.20e7.39
[10H, m, aromatics]; 8.08 (m) [1H, br s, NHCH2Ph (at rt: br t
at 8.39, J¼5.8)]; 8.39 (m) [1H, br s, NHCH2Ph (at rt: br t at
8.70, J¼5.8)]. 13C NMR (75 MHz): 26.8 (M ), 27.8 (m), 29.3
(m), and 30.3 (M ) [2C, CH2 pyrrolidine]; 33.5 (M ) and 33.6
(m) [NCOCH2]; 36.2 (M ) and 36.4 (m) [CH2NHZ]; 41.7 (m)
and 42.2 (M ) [NHCH2Ph]; 51.8 (M ) and 52.5 (m) [OCH3];
59.0 (M ) and 59.4 (m), 60.16 (m) and 60.19 (M ) [2C, CH pyr-
rolidine]; 65.2 [OCH2Ph]; 126.6, 126.8, 127.1, 127.75,
127.71, 128.2, and 128.3 [10C, aromatic CH]; 137.1, 139.1
(M ), and 139.4 (m) [2C, aromatic C]; 155.9 [CO (Z)]; 169.6
(M ) and 169.8 (m), 171.1 (M ) and 171.3 (m), 172.2 (M ) and
172.5 (m) [3C, CO].
4.12.3. Stereoisomer (5R,8S,10aR) 23
Chromatography with CH2Cl2/AcOEt 4:6 gave 23 as
a white foam in 81% yield. Rf 0.41 (CH2Cl2/AcOEt 4:6, A,
C, and D). Anal. Found: C, 61.30; H, 6.70; N, 9.80.
C22H29N3O6 requires C, 61.24; H, 6.77; N, 9.74. [a]D20
ꢀ67.6 (c 1.04, EtOH). IR: nmax 3417, 2957, 1716, 1672,
1621, 1483, 1368, 1156, and 1097. GCeMS: unsuitable for
this analysis. 1H NMR (300 MHz, DMSO-d6, rt: rotamers ratio
cannot be determined): 1.40 [9H, s, OC(CH3)3]; 1.55e2.30
[4H, m, CH2 pyrrolidine]; 2.81 and 3.00 [2H, AB part of an
ABX system, CH2CO, JAB¼13.1, JAX¼5.8, JBX¼8.7];
3.92e5.08 [7H, m, CH2Ph, CH2O, CH pyrrolidine,
CHNHBoc]; 7.16e7.34 [5H, m, aromatics]; 7.54 [1H, br s,
NHBoc]; 8.17 [1H, br t, NHCH2Ph, J¼5.6]. 13C NMR
(75 MHz): 26.7, 28.8, and 29.0 [2C, CH2 pyrrolidine]; 28.0
[3C, OC(CH3)3]; 38.0 (m) and 38.1 (M ), 41.7 [2C, NHCH2Ph,
CH2CO]; 54.7, 55.8, and 62.2 [3C, CH pyrrolidine,
CHNHBoc]; 69.6 [CH2O]; 78.8 [OC(CH3)3]; 126.6 [CH
para (Ph)]; 126.9 [2C, CH ortho (Ph)]; 128.2 [2C, CH meta
(Ph)]; 139.3 [C (Ph)]; 154.8 [CO (Boc)]; 167.7, 170.8, and
171.5 [3C, CO].
4.13.2. Compound 33
Chromatography with PE/AcOEt 1:9/AcOEt/Me2CO
95:5 gave 32 as a yellow oil in 68% overall yield. Rf 0.23
(PE/AcOEt 1:9, C). Anal. Found: C, 64.20; H, 6.30; N,
8.85. C25H29N3O6 requires C, 64.23; H, 6.25; N, 8.99. [a]D20
þ16.71 (c 1.12). IR: nmax 3440, 3005, 1725, 1653, 1189,
and 1073. GCeMS: unsuitable for this analysis. 1H NMR
(300 MHz, DMSO-d6, rt: 71:29 mixture of rotamers, one
highly prevailing at 90 ꢁC) at 90 ꢁC: 1.78e2.55 [6H, m, CH2
pyrrolidine, NCOCH2]; 3.26 [2H, center of m, CH2NHZ];
3.65 [3H, 2s, OCH3]; 4.29e4.49 [4H, m, CH, NHCH2Ph];
5.04 [2H, s, OCH2Ph]; 6.77 [1H, br s, NHZ]; 7.21e7.40
[10H, m, aromatics]; 8.20 [1H, br s, NHCH2Ph (at rt: 2br t
at 8.03 and 8.38, J¼6.0, 6.0)]. 13C NMR (75 MHz): 27.5
(M ), 28.1 (m), 30.6 (m), and 30.7 (M ) [2C, CH2 pyrrolidine];
33.4 (M ) and 33.6 (m) [NCOCH2]; 36.1 (M ) and 36.4 (m)
[CH2NHZ]; 41.8 (m) and 42.3 (M ) [NHCH2Ph]; 52.4 (M )
and 52.7 (m) [OCH3]; 59.5 (M ) and 59.6 (m), 61.4 (m) and
61.5 (M ) [2C, CH pyrrolidine]; 65.2 [OCH2Ph]; 126.68,
126.74, 126.9, 127.0, 127.7, 128.2, 128.3, and 128.4 [10C,
aromatic CH]; 137.1, 138.7 (M ), and 139.1 (m) [2C, aromatic
C]; 155.9 [CO (Z)]; 170.3 (M ) and 170.5 (m), 171.0 (m) and
171.1 (M ), 173.4 (m) and 174.2 (M ) [3C, CO].
4.13. General procedure for Jones oxidation and methyl
ester formation
(a) Jones oxidation: a solution of the appropriate alcohol
(53.42 mmol) was dissolved in dry acetone (5 ml) and cooled
to 0 ꢁC; then Jones reagent was added dropwise (3 M equiv)
and the solution stirred at 0 ꢁC for 2e3 h until disappearance
of the starting material. A too long reaction time must be
avoided in order to get a satisfactory yield. MeOH was added
to reduce excess reagent and the reaction was stirred addi-
tional 30 min at rt. After dilution with 5% NH4HPO4 saturated
with NaCl, an extraction with AcOEt was performed. Due to
the high affinity for the aqueous layer the extraction was

L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
1129
4.13.3. Compound 38
(M ), 170.3 (m), 170.6 (M ), 170.8 (m), 172.6 (M ), and 173.2
(m) [3C, CO].
Chromatography with PE/AcOEt 3:7/2:8 gave 38 as
a pale yellow oil in 33% overall yield. Rf 0.50 (PE/AcOEt
2:8, A and C). Anal. Found: C, 62.00; H, 6.45; N, 9.65.
C30H38N4O8 requires C, 61.84; H, 6.57; N, 9.62. [a]D20
þ41.9 (c 1.00). IR: nmax 3431, 3001, 1712, 1660, 1491,
1425, 1369, 1215, and 1070. GCeMS: unsuitable for this anal-
4.14. Formation of bicyclic derivatives 40 and 41
These compounds were obtained through the Jones oxida-
tion of alcohols 36 and 37 (see Section 4.13), together with
the expected carboxylic acids and have been separated from
methyl esters 38 and 39 as described above.
1
ysis. H NMR (300 MHz, DMSO-d6, rt: four rotamers can be
detected with the two highly prevailing (z80%) in a 58:41 ra-
tio; a mixture of rotamers with very broad signals is present
even at 120 ꢁC): 1.39 and 1.41 [9H, 2s, C(CH3)3]; 1.78e
4.77 [11H, m, CH2 pyrrolidine, NHCH2Ph, CH2OH,
CH2NHZ, CH]; 3.58 and 3.74 [3H, 2s, OCH3]; 4.97e5.10
[2H, m, OCH2Ph]; 6.88 and 7.11 [1H, 2br d, NHZ, J¼8.1,
7.2]; 6.90 and 7.05 [1H, 2br t, NHBoc, J¼5.4, 5.7]; 7.20e
7.39 [10H, m, aromatics]; 8.09 and 8.69 [1H, 2br t, NHCH2Ph,
J¼5.8, 5.4)]. 13C NMR (75 MHz) (only the signals of the two
highly prevailing rotamers have been reported): 26.6 (M ), 27.6
(m), 29.4 (M ), and 30.5 (m) [2C, CH2 pyrrolidine]; 27.95 (m)
and 28.03 (M ) [3C, OC(CH3)3]; 41.1, 41.8, and 42.5 [2C,
CH2N]; 50.8 (M ) and 51.4 (m) [CHNHBoc]; 51.6 (M ) and
52.6 (m) [OCH3]; 59.3, 60.1 (M ), and 60.5 (m) [2C, CH pyr-
rolidine]; 65.2 (m) and 65.3 (M ) [CH2O]; 78.3 (M ) and 78.7
(m) [OC(CH3)3]; 126.6, 126.7, 127.0, 127.2, 127.59, 127.62,
127.7, 128.18, and 128.24 [10C, aromatic CH]; 136.9 (M )
and 137.0 (m), 139.1 (M ) and 139.2 (m) [2C, aromatic C];
155.1, 155.6, and 156.0 [2C, CO (Z, Boc)]; 169.8, 169.9,
170.6, 171.2, 171.6, and 172.2 [3C, CO].
4.14.1. (3S,6R,8aR)-N-Benzyl-3-{[(benzyloxycarbonyl)-
amino]methyl}-2-(tert-butoxycarbonyl)-octahydro-1,4-
dioxo-pyrrolo[1,2-a]pyrazine-6-carboxamide 40
Compound 40, as a pale yellow oil, was obtained in 45%
yield. Rf 0.35 (PE/AcOEt 2:8, A and C). Anal. Found: C,
63.40; H, 6.35; N, 10.25. C29H34N4O7 requires C, 63.26; H,
6.22; N, 10.18. [a]D20 þ115.5 (c 1.39). IR: nmax 3430, 3353,
3002, 1780, 1723, 1671, 1370, 1192, and 1145. GCeMS: un-
suitable for this analysis. 1H NMR (300 MHz, DMSO-d6):
1.42 [9H, s C(CH3)3]; 1.69e2.25 [4H, m, CH2 pyrrolidine];
3.49 [2H, center of m, CH2NHZ; at 90 ꢁC: AB part of an
ABX system at 3.53 and 3.61, JAB¼9.4, JAX¼4.2, JBX¼4.0];
4.23e4.31 [2H, m, NHCH2Ph; at 90 ꢁC: AB part of an ABX
system at 4.32 and 4.35, JAB¼15.3, JAX¼5.9, JBX¼5.8];
4.37 and 4.48 [2H, 2t, CH pyrrolidine, J¼7.5, 7.8]; 4.67
[1H, t, CHNHBoc, J¼6.6]; 4.88 and 4.93 [2H, AB system,
OCH2Ph, JAB¼12.6]; 7.22e7.33 [10H, m, aromatics]; 7.59
[1H, br t, NHZ, J¼6.3]; 8.28 [1H, br t, NHBn, J¼6.0]. 13C
NMR (75 MHz): 27.4 [3C, OC(CH3)3]; 27.7 and 28.0 [2C,
CH2 pyrrolidine]; 41.2 [CH2NHZ]; 41.8 [NHCH2Ph]; 59.8
and 60.3 [2C, CH pyrrolidine]; 60.1 [CHNHBoc]; 65.6
[CH2O]; 83.2 [OC(CH3)3]; 126.6, 126.7, 127.7, 127.8,
128.16, and 128.25 [10C, aromatic CH]; 136.6 and 139.2
[2C, aromatic C]; 149.8 [CO (Boc)]; 156.6 [2C, CO (Z)];
163.5 and 166.3 [2C, CO ring]; 170.2 [CONHBn].
4.13.4. Compound 39
Chromatography with PE/AcOEt 3:7 gave 39 as a pale yel-
low oil in 27% overall yield. Rf 0.45 (PE/AcOEt 3:7, A and C).
Anal. Found: C, 61.80; H, 6.60; N, 9.75. C30H38N4O8 requires
C, 61.84; H, 6.57; N, 9.62. [a]2D0 þ2.18 (c 1.05). IR: nmax 3427,
2996, 1722, 1659, 1488, 1419, 1368, 1246, 1155, and 1074.
1
GCeMS: unsuitable for this analysis. H NMR (300 MHz,
DMSO-d6, rt: five rotamers can be detected with the two
highly prevailing (z80%) in a 64:36 ratio; a mixture of ro-
tamers with very broad signals is present even at 120 ꢁC):
1.366 and 1.373 [9H, 2s, C(CH3)3]; 1.58e4.66 [11H, m,
CH2 pyrrolidine, NHCH2Ph, CH2OH, CH2NHZ, CH]; 3.36
and 3.44 [3H, 2s, OCH3]; 4.91e5.16 [2H, m, OCH2Ph];
7.04 [1H, br d, NHZ one rotamer, J¼7.2]; 7.10 [1H, br t,
NHBoc one rotamer, J¼5.8]; 7.15e7.40 [10H, m, aromatics,
NHZ and NHBoc other rotamers]; 8.09 and 8.69 [1H, 2br t,
NHCH2Ph, J¼5.8, 5.4]. 13C NMR (75 MHz) (only the signals
of the two highly prevailing rotamers have been reported):
26.9 (M ), 27.3 (m), 29.8 (m), and 30.4 (M ) [2C, CH2 pyrrol-
idine]; 27.8 (m) and 28.0 (M ) [3C, OC(CH3)3]; 41.3, 41.5,
41.8, and 42.8 [2C, CH2N]; 51.6 (m) and 52.1 (M )
[CHNHBoc]; 51.8 (M ) and 52.8 (m) [OCH3]; 59.7 (m), 60.3
(M ), 61.1 (M ), and 61.8 (M ) [2C, CH pyrrolidine]; 65.4
[CH2O]; 78.6 (M ) and 79.0 (m) [OC(CH3)3]; 126.58,
126.64, 126.75, 126.84, 127.2, 127.6, 127.67, 127.74, 128.1,
128.2, and 128.3 [10C, aromatic CH]; 136.79 (m) and
136.84 (M ), 138.6 (M ) and 139.1 (m) [2C, aromatic C];
155.2 (M ), 155.4 (m), and 156.2 [2C, CO (Z, Boc)]; 169.8
4.14.2. Stereoisomer (3S,6S,8aR) 41
Compound 41, as a pale yellow oil, was obtained in 31%
yield. Rf 0.35 (PE/AcOEt 3:7, A and C). Anal. Found: C,
63.35; H, 6.30; N, 10.30. C29H34N4O7 requires C, 63.26; H,
6.22; N, 10.18. [a]D20 þ53.8 (c 0.72). IR: nmax 3441, 3018,
2987, 1781, 1727, 1675, 1370, 1249, 1145, and 1051. GCe
MS: unsuitable for this analysis. 1H NMR (300 MHz,
DMSO-d6): 1.46 [9H, s C(CH3)3]; 1.85e2.16 [4H, m, CH2
pyrrolidine]; 3.51 [2H, center of m, CH2NHZ]; 4.25 and
4.31 [2H, AB part of an ABX system, NHCH2Ph,
JAB¼15.9, JAX¼5.8, JBX¼5.6]; 4.36 [1H, br d, CH pyrro-
lidine, J¼8.4]; 4.52 [1H, br dd, CH pyrrolidine, J¼9.8, 5.8];
4.71 [1H, t, CHNHBoc, J¼6.8]; 5.02 [2H, s, OCH2Ph];
7.21e7.40 [10H, m, aromatics]; 7.63 [1H, br t, NHZ,
J¼6.3]; 8.62 [1H, br t, NHBn, J¼6.0]. 13C NMR (75 MHz):
26.9 and 28.6 [2C, CH2 pyrrolidine]; 27.4 [3C, OC(CH3)3];
40.7 [CH2NHZ]; 41.9 [NHCH2Ph]; 58.7, 59.6, and 60.4
[3C, CH pyrrolidine, CHNHBoc]; 65.5 [CH2O]; 83.2
[OC(CH3)3]; 126.7, 126.9, 127.7, 127.8, 128.2, and 128.3
[10C, aromatic CH]; 136.8 and 139.1 [2C, aromatic C];

1130
L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
149.8 [CO (Boc)]; 156.2 [CO (Z)]; 163.2 and 166.6 [2C, CO
ring]; 170.3 [CONHBn].
CH2CHH pyrrolidine]; 2.34e2.48 [2H, m, CH2CHH pyrrol-
idine, CONHCH2CHH]; 2.69 [1H, ddd, CONHCH2CHH,
J¼17.1, 5.4, 3.0]; 3.06e3.18 [1H, m, CONHCHHCH2]; 3.59
[1H, center of m, CONHCHHCH2]; 4.22 and 4.29 [2H, AB
part of an ABX system, CH2Ph, JAB¼15.4, JAX¼5.6,
JBX¼5.8]; 4.49 [1H, dd, CHCONHBn, J¼8.4, 2.7]; 4.70
[1H, t, CHCONHCH2, J¼7.5]; 7.19e7.34 [5H, m, aromatics];
7.96 [1H, br t, NHCH2CH2, J¼5.1]; 8.29 [1H, br t, NHCH2Ph,
J¼5.8]. 13C NMR (75 MHz): 26.7 and 27.2 [2C, CH2 pyrrol-
idine]; 36.0 [CONHCH2CH2]; 36.4 [CONHCH2CH2]; 41.8
[NHCH2Ph]; 57.7 [CHCONHCH2]; 61.0 [CHCONHBn];
126.5 [CH para of Ph]; 126.8 [2C, CH ortho of Ph]; 128.1
[2C, CH meta of Ph]; 139.5 [aromatic C]; 169.1, 170.1, and
171.0 [3C, CO].
4.15. General procedure for diazepine-1,5-dione ring
formation
(a) Carbobenzyloxy group removal: a solution of the sub-
strate in MeOH was treated with Pd/C (5e10% w/w) and
hydrogenated for 1e3 h. After catalyst filtration and solvent
removal, crude amine was used as such for the following reac-
t
tion. (b) Cyclization: a solution of crude amine in dry BuOH
(z0.2 M) was refluxed for 38e45 h, in some cases (prepara-
tion of 34, 35, 42, and 43) in the presence of Et3N (concentra-
tion in the reaction medium: 0.5 M). Solvent removal under
reduced pressure was directly followed by chromatography.
4.15.3. (4S,7R,9aR)-N-Benzyl-4-[(tert-butoxycarbonyl)-
amino]-octahydro-1,5-dioxo-1H-pyrrolo[1,2-a][1,4]-
diazepin-7-carboxamide 42
4.15.1. (7R,9aR)-N-Benzyl-octahydro-1,5-dioxo-1H-
pyrrolo[1,2-a][1,4]diazepine-7-carboxamide 34
Chromatography with CH2Cl2/MeOH 9:1/8:2 gave 34 as
a white solid in 76% overall yield. Rf 0.35 (CH2Cl2/MeOH 9:1,
B). Anal. Found: C, 63.65; H, 6.40; N, 13.75. C16H19N3O3 re-
quires C, 63.77; H, 6.36; N, 13.94. [a]2D0 þ38.4 (c 0.74,
CH2Cl2/MeOH 9:1). Mp: 239.4e241.0 ꢁC (CH2Cl2/MeOH).
IR (KBr): nmax 3235, 1684, 1653, 1621, 1564, 1435, 1395,
and 1034. GCeMS: tR 12.21; m/z 301 (Mþ, 30), 168 (48),
167 (100), 139 (7.7), 126 (5.8), 125 (30), 122 (11), 113
(28), 106 (34), 97 (18), 96 (10), 91 (52), 70 (9.7), 69 (15),
68 (66), 65 (9.2), 55 (18), 43 (6.7), 42 (5.0), 41 (16), 39
(6.0). 1H NMR (300 MHz, DMSO-d6): 1.76e2.00 [3H, m,
CH2CHH pyrrolidine]; 2.37e2.49 [2H, m, CH2CHH pyrrol-
idine, CONHCH2CHH]; 2.73 [1H, dt, CONHCH2CHH,
J¼17.7, 3.8]; 3.03e3.14 [1H, m, CONHCHHCH2]; 3.70
[1H, center of m, CONHCHHCH2]; 4.27 and 4.32 [2H, AB
This compound has been prepared by the hydrogenolysise
cyclization procedure from: (a) purified 38 (65%); (b) purified
40 (48%); (c) a one-pot procedure (56% from 36). Chromatog-
raphy with CH2Cl2/MeOH 95:5 gave 42 as a white solid. Rf
0.33 (CH2Cl2/MeOH 93:7, A and B). Anal. Found: C, 60.65;
H, 6.75; N, 13.60. C21H28N4O5 requires C, 60.56; H, 6.78;
N, 13.45. [a]2D0 þ93.1 (c 0.52, CH2Cl2/MeOH 9:1) from (a)
and [a]2D0 þ95.1 (c 0.41, CH2Cl2/MeOH 9:1) from (b). Mp:
198.1e199.7 ꢁC (CH2Cl2/MeOH). IR (KBr): nmax 3310,
2973, 1684, 1546, 1491, 1444, 1367, 1251, 1166, and 1061.
GCeMS: unsuitable for this analysis. HPLCeMS (exact
mass 416.2): m/z 417.1 (MþþH), 439.1 (MþþNa), 455.1
1
(MþþK), 855.0 (2MþþNa); MS2 (417.1): 361.1, 317.0. H
NMR (300 MHz, DMSO-d6) at 90 ꢁC: 1.43 [9H, s,
C(CH3)3]; 1.81e2.10 [3H, m, CH2CHH pyrrolidine]; 2.49e
2.58 [1H, m, CH2CHH pyrrolidine]; 3.12 [1H, ddd,
CHHCHNHBoc, J¼13.8, 8.4, 3.6]; 3.62 [1H, dt,
CHHCHNHBoc, J¼13.5, 4.5]; 4.31 [2H, d, CH2Ph, J¼6.3];
4.46 [1H, dd, CHCONHBn, J¼8.1, 2.4]; 4.73 [1H, ddd,
CHNHBoc, J¼12.3, 7.2, 4.5]; 4.88 [1H, dd, CHCONHCH2,
J¼7.8, 2.1]; 6.42 [1H, br d, NHBoc, J¼6.0 (at rt: d at 6.93,
J¼7.5)]; 7.20e7.34 [5H, m, aromatics]; 7.53 [1H, br s,
NHCH2CH (at rt: br s at 7.83)]; 8.13 [1H, br s, NHCH2Ph
(at rt: br t at 8.44, J¼6.0)]. 13C NMR (75 MHz): 25.7 and
28.0 [2C, CH2 pyrrolidine]; 28.1 [3C, OC(CH3)3]; 41.8
[NHCH2Ph]; 43.6 [CONHCH2CH]; 51.8 [CHNHBoc]; 58.1
[CHCONHCH2]; 61.4 [CHCONHBn]; 78.3 [OC(CH3)3];
126.6 [CH para of Ph]; 126.7 [2C, CH ortho of Ph]; 128.2
[2C, CH meta of Ph]; 139.3 [aromatic C]; 154.8 [CO (Boc)];
168.3, 169.6, and 170.8 [3C, CO].
part of an ABX system, CH2Ph, JAB¼13.8, JAX¼4.1, JBX
¼
3.4]; 4.44 [1H, dd, CHCONHBn, J¼7.2, 1.2]; 4.92 [1H, br
d, CHCONHCH2, J¼5.7]; 7.20e7.34 [5H, m, aromatics];
7.98 [1H, br t, NHCH2CH2, J¼5.6]; 8.44 [1H, br t, NHCH2Ph,
J¼5.8]. 13C NMR (75 MHz): 25.6 and 27.6 [2C, CH2 pyrrol-
idine]; 35.8 [CONHCH2CH2]; 36.7 [CONHCH2CH2]; 41.8
[NHCH2Ph]; 56.2 [CHCONHCH2]; 61.7 [CHCONHBn];
126.6 [CH para of Ph]; 126.7 [2C, CH ortho of Ph]; 128.2
[2C, CH meta of Ph]; 139.4 [aromatic C]; 168.8, 171.1, and
171.2 [3C, CO].
4.15.2. Stereoisomer (7S,9aR) 35
Chromatography with CH2Cl2/MeOH 9:1/8:2 gave 35 as
a white solid in 70% overall yield. Rf 0.35 (CH2Cl2/MeOH 9:1,
B). Anal. Found: C, 63.85; H, 6.45; N, 13.80. C16H19N3O3
requires C, 63.77; H, 6.36; N, 13.94. [a]2D0 ꢀ25.20 (c 0.36,
CH2Cl2/MeOH 9:1). Mp: 230.8e233.8 ꢁC (CH2Cl2/MeOH).
IR (KBr): nmax 3272, 1699, 1651, 1609, 1557, 1440, 1397,
1322, 1292, 1241, and 1208. GCeMS: tR 12.40; m/z 301
(Mþ, 27), 169 (5.5), 168 (53), 167 (100), 139 (9.4), 126
(6.5), 125 (33), 122 (12), 113 (30), 106 (39), 97 (20), 96
(11), 92 (5.4), 91 (60), 77 (5.1), 70 (10), 69 (17), 68 (72),
65 (11), 56 (6.2), 55 (20), 43 (6.7), 42 (5.5), 41 (17), 39
(6.5). 1H NMR (300 MHz, DMSO-d6): 1.81e2.05 [3H, m,
4.15.4. Stereoisomer (4S,7S,9aR) 43
This compound has been prepared by the hydrogenolysise
cyclization procedure from: (a) purified 39 (66%); (b) purified
41 (49%); (c) a one-pot procedure (46% from 37). Chromatog-
raphy with CH2Cl2/MeOH 93:7/9:1 gave 43 as a white solid.
Rf 0.30 (CH2Cl2/MeOH 93:7, A and B). Anal. Found: C,
60.70; H, 6.85; N, 13.55. C21H28N4O5 requires C, 60.56; H,
6.78; N, 13.45. [a]2D0 þ2.8 (c 0.50, CH2Cl2/MeOH 9:1) from

L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
1131
(a) and [a]2D0 þ2.2 (c 0.63, CH2Cl2/MeOH 9:1) from (b). Mp:
130.1e132.3 ꢁC (CH2Cl2/MeOH). IR (KBr): nmax 3320, 2974,
1692, 1493, 1435, 1367, 1241, 1171, 1062, and 1028. GCe
MS: unsuitable for this analysis. HPLCeMS (exact mass
416.2): m/z 417.1 (MþþH), 439.2 (MþþNa), 455.1
(MþþK), 833.0 (2MþþH), 855.2 (2MþþNa); MS2 (417.1):
255 (100), 167 (6.8), 156 (29), 125 (5.9), 113 (6.0), 99
(5.1), 97 (6.9), 82 (15), 80 (6.1), 75 (35), 73 (32), 68 (23),
59 (16), 58 (5.7), 57 (6.8), 56 (6.8), 55 (23), 47 (5.2), 45
(8.4), 43 (8.7), 42 (7.8), 41 (20), 39 (5.0). 1H NMR
(300 MHz, DMSO-d6): 0.01 [6H, s, Si(CH3)2]; 0.86 [9H, s,
SiC(CH3)3]; 1.70e1.91 [3H, m, CH2CHH pyrrolidine];
2.33e2.46 [2H, m, CH2CHH pyrrolidine, CONHCH2CHH];
2.66 [1H, ddd, CONHCH2CHH, J¼17.4, 5.7, 3.0]; 3.06 [1H,
dq, CONHCHHCH2, J¼15.3, 5.1]; 3.31 and 3.58 [2H, AB
1
361.1, 317.1. H NMR (300 MHz, DMSO-d6) at 90 ꢁC: 1.42
[9H, s, C(CH3)3]; 1.84e2.10 [3H, m, CH2CHH pyrrolidine];
2.36e2.47 [1H, m, CH2CHH pyrrolidine]; 3.19 [1H, ddd,
CHHCHNHBoc, J¼13.2, 9.6, 2.7]; 3.43 [1H, ddd,
CHHCHNHBoc, J¼13.5, 4.8, 3.9]; 4.27 and 4.32 [2H, AB
part of an ABX system, CH2Ph, JAB¼15.5, JAX¼5.9,
JBX¼6.3]; 4.54 [1H, dd, CHCONHBn, J¼8.4, 4.5]; 4.34
[1H, ddd, CHNHBoc, J¼9.9, 7.2, 3.3]; 4.76 [1H, t,
CHCONHCH2, J¼7.0]; 6.49 [1H, br s, NHBoc (at rt: d at
7.09, J¼7.8)]; 7.20e7.34 [5H, m, aromatics]; 7.54 [1H, br s,
NHCH2CH (at rt: br t at 7.86, J¼3.8)]; 8.02 [1H, br s,
NHCH2Ph (at rt: br t at 8.32, J¼6.2)]. 13C NMR (75 MHz):
27.0 and 27.6 [2C, CH2 pyrrolidine]; 28.1 [3C, OC(CH3)3];
41.8 [NHCH2Ph]; 43.2 [CONHCH2CH]; 51.8 [CHNHBoc];
58.7 [CHCONHCH2]; 61.2 [CHCONHBn]; 78.3 [OC(CH3)3];
126.5 [CH para of Ph]; 126.7 [2C, CH ortho of Ph]; 128.1
[2C, CH meta of Ph]; 139.3 [aromatic C]; 154.9 [CO (Boc)];
168.7, 168.9, and 170.6 [3C, CO].
part of an ABX system, CH2O, JAB¼8.8, JAX¼8.2, JBX
¼
5.0]; 3.58 [1H, center of m, CONHCHHCH2]; 4.14 [1H, br
dt, CHCH2O, J¼7.4, 2.7]; 4.64 [1H, dd, CHCONH, J¼9.0,
7.5]; 7.95 [1H, br t, NH, J¼5.0]. 13C NMR (75 MHz): ꢀ5.5
[2C, Si(CH3)2]; 17.9 [SiC(CH3)3]; 24.2 and 25.5 [2C, CH2
pyrrolidine]; 25.7 [3C, SiC(CH3)3]; 36.0 [CONHCH2CH2];
36.6 [CONHCH2CH2]; 57.0 [CHCONHCH2]; 59.3
[CHCH2O]; 61.8 [CH2O]; 169.0 and 170.6 [2C, CO].
4.16. Boc introduction on compounds 14 and 15h
A solution of 14h or 15h (678 mg, 1.19 mmol) in dry
CH2Cl2 (18 ml) was cooled to 0 ꢁC and treated with Et3N
(249 ml, 1.79 mmol), di-tert-butyl dicarbonate (287 ml,
1.25 mmol), and DMAP (22 mg, 17.85 mmol). After 10 min
the reaction was allowed to stir at rt and, after 3.5 h, usually
an addition of a substoichiometric amount of all the reagents
was necessary (0.2e0.5 M equiv). After stirring overnight
the solvent was evaporated and the crude was directly purified
by chromatography.
4.15.5. (7R,9aR)-7-{[(tert-Butyldimethylsilyl)oxy]methyl}-
hexahydro-2H-pyrrolo[1,2-a][1,4]diazepine-1,5-dione 58
Chromatography with CH2Cl2/MeOH 99:1/95:5 gave 58
as a pale yellow oil in 98% overall yield. Rf 0.31 (CH2Cl2/
MeOH 95:5, B). Anal. Found: C, 57.80; H, 9.15; N, 8.80.
C15H28N2O3Si requires C, 57.66; H, 9.03; N, 8.96. [a]D20
þ65.0 (c 1.02). IR: nmax 3414, 3004, 2948, 1682, 1620, 1390,
1189, 1108, and 1045. GCeMS: tR 9.48; m/z 312 (Mþ, 0.058),
257 (5.8), 256 (19), 255 (100), 167 (8.8), 156 (21), 82 (6.2),
75 (13), 73 (11), 68 (8.6), 55 (6.3). 1H NMR (300 MHz,
DMSO-d6): 0.03 and 0.04 [6H, 2s, Si(CH3)2]; 0.86 [9H, s,
SiC(CH3)3]; 1.60e2.08 [3H, m, CH2CHH pyrrolidine]; 2.34e
2.46 [2H, m, CH2CHH pyrrolidine, CONHCH2CHH]; 2.72
[1H, dt, CONHCH2CHH, J¼17.4, 4.2]; 3.05 [1H, center of m,
CONHCHHCH2]; 3.49 and 3.69 [2H, AB part of an ABX sys-
tem, CH2O, JAB¼9.6, JAX¼7.5, JBX¼3.3]; 3.60 [1H, ddd,
CONHCHHCH2, J¼15.6, 7.5, 4.5]; 4.06 [1H, dt, CHCH2O,
J¼7.5, 3.3]; 4.73 [1H, d, CHCONH, J¼8.4]; 7.90 [1H, br t,
NH, J¼5.1]. 13C NMR (75 MHz): ꢀ5.5 [2C, Si(CH3)2]; 17.8
[SiC(CH3)3]; 24.6 and 24.7 [2C, CH2 pyrrolidine]; 25.7 [3C,
SiC(CH3)3]; 35.9 [CONHCH2CH2]; 36.7 [CONHCH2CH2];
55.9 [CHCONHCH2]; 60.0 [CHCH2O]; 61.5 [CH2O]; 168.4
and 171.1 [2C, CO].
4.16.1. Compound 56
Chromatography with PE/AcOEt 8:2/1:1 gave 56 as an or-
ange foam in 85% yield. Rf 0.71 (PE/AcOEt 1:1, A and C). Anal.
Found: C, 62.90; H, 7.80; N, 6.30. C35H51N3O8Si requires C,
62.75; H, 7.67; N, 6.27. [a]2D0 þ59.9 (c 1.20). IR: nmax 3447,
2949, 1711, 1626, 1239, 1148, 1084, and 833. GCeMS: unsuit-
able for this analysis. 1H NMR (300 MHz, DMSO-d6, rt: 67:33
mixture of rotamers, remains even at 90 ꢁC) at 90 ꢁC: 0.03,
0.055, and 0.065 [6H, 3s, Si(CH3)2]; 0.89 [9H, s, SiC(CH3)3];
1.39 and 1.40 [2H, 2s, OC(CH3)3]; 1.83e2.58 [6H, m, CH2 pyr-
rolidine, NCOCH2]; 3.25 [2H, center of m, CH2NHZ]; 3.54e
3.79 [2H, m, CHCH2OSi]; 3.78 [3H, s, OCH3]; 4.02e4.10
[1H, m, CHCH2OSi]; 5.04 and 5.04 [2H, AB system, OCH2Ph,
J¼13.2]; 5.10 (M ) and 5.40 (m) [1H, 2d, CHCONH, J¼9.0
both]; 6.68 and 6.78 [1H, 2br s, NHZ, (at rt: 2br t at 7.15 and
7.21, J¼5.7, 6.0)]; 6.92 [2H, dt, CH meta to OMe, J¼9.0,
2.7]; 7.07 [2H, apparent d, CH ortho to OMe, J¼8.7]; 7.27e
7.38 [5H, m, aromatics]. 13C NMR (75 MHz): ꢀ5.6, ꢀ5.5,
and ꢀ5.4 [2C, Si(CH3)2]; 17.8 [C(CH3)3]; 24.5 (m), 26.7 (M ),
27.1 (M ), and 29.5 (m) [2C, CH2 pyrrolidine]; 25.7 [3C,
SiC(CH3)3]; 27.4 [3C, OC(CH3)3]; 33.6 (M ) and 34.1 (m)
[NCOCH2]; 36.6 (m) and 36.7 (M ) [CH2NHZ]; 55.2 [OCH3];
59.0 (M ) and 59.1 (m) [CHCH2OSi]; 60.5 (M ) and 62.0 (m)
[CHCONH]; 64.3 [CH2OSi]; 65.1 [OCH2Ph]; 82.8 (M ) and
83.4 (m), 113.8 (M ) and 113.9 (m) [2C, CH ortho to OMe];
127.6, 127.7, and 128.2 [5C, CH of Ph]; 129.1 (M ) and
129.2 (m) [2C, CH meta to OMe]; 130.9 (m) and 131.4 (M )
4.15.6. Stereoisomer (7S,9aR) 59
Chromatography with CH2Cl2/MeOH 99:1/95:5 gave 59
as a pale yellow solid in 86% overall yield. Rf 0.32 (CH2Cl2/
MeOH 95:5, B). Anal. Found: C, 57.75; H, 8.90; N, 8.85.
C15H28N2O3Si requires C, 57.66; H, 9.03; N, 8.96. [a]D20
þ6.4 (c 0.46). Mp: 102.6e104.0 ꢁC (CH2Cl2/MeOH). IR:
nmax 3410, 3003, 2950, 1651, 1418, 1393, and 1096. GCe
MS: tR 9.58; m/z 297 (Mþꢀ15, 2.6), 257 (5.4), 256 (19),

1132
L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
[C-NBoc]; 137.0 [C of Ph]; 151.9 (m) and 152.3 (M ), 155.9,
158.2 (M ) and 158.4 (m) [2C, C-OMe, CO (Z, Boc)]; 169.4
(M ) and 169.6 (m), 174.5 (M ) and 174.6 (m) [2C, CO].
125 (28), 122 (11), 113 (27), 100 (28), 97 (28), 96 (12), 82
(8.5), 72 (6.3), 70 (7.9), 69 (15), 68 (72), 57 (7.4), 56 (10), 55
1
(31), 44 (7.6), 43 (10), 42 (12), 41 (23), 39 (9.6). H NMR
(300 MHz, DMSO-d6): 1.56e2.06 [3H, m, CH2CHH pyrro-
lidine]; 2.32e2.44 [2H, m, CH2CHH pyrrolidine, CONH-
CH2CHH]; 2.73 [1H, dt, CONHCH2CHH, J¼17.4, 4.2]; 3.04
[1H, center of m, CONHCHHCH2]; 3.24e3.54 [2H, m, CH2O];
3.61 [1H, center of m, CONHCHHCH2]; 4.03 [1H, dt, CHCH2O,
J¼7.6, 3.6]; 4.75 [1H, br d, CHCONH, J¼8.1]; 4.79 [1H, t, OH,
J¼5.7]; 7.90[1H, brt, NH, J¼5.0]. 13C NMR (75 MHz): 24.7and
24.8 [2C, CH2 pyrrolidine]; 35.9 [CONHCH2CH2]; 36.7
[CONHCH2CH2]; 55.9 [CHCONHCH2]; 60.3 [CH2O]; 60.6
[CHCH2O]; 168.5 and 171.2 [2C, CO].
4.16.2. Compound 57
Chromatography with PE/AcOEt 8:2/1:1 gave 57 as an
orange oil in an estimated 55% (based on NMR) (73% on un-
recovered 15h) yield. An analytical sample of 57 was obtained
through an additional chromatography. Rf 0.51 (PE/AcOEt 6:4,
A and C). Anal. Found: C, 62.80; H, 7.60; N, 6.35.
C35H51N3O8Si requires C, 62.75; H, 7.67; N, 6.27. [a]D20
ꢀ77.5 (c 0.91). IR: nmax 3442, 3021, 1712, 1626, 1421,
1214, 1147, and 1087. GCeMS: unsuitable for this analysis.
1H NMR (300 MHz, DMSO-d6, rt: z3:1 mixture of rotamers)
at 90 ꢁC: 0.06 [6H, s, Si(CH3)2]; 0.89 [9H, s, SiC(CH3)3]; 1.39
[2H, s, OC(CH3)3]; 1.80e2.76 [6H, m, CH2 pyrrolidine,
NCOCH2]; 3.28 [2H, br q, CH2NHZ, J¼6.4]; 3.55e4.10
[3H, m, CHCH2OSi]; 3.80 [3H, s, OCH3]; 5.00e5.40 [3H,
m, OCH2Ph, CHCONH]; 6.81 [1H, br s, NHZ, (at rt: br t at
7.22 (M ), J¼5.4)]; 6.94 [2H, dt, CH meta to OMe, J¼9.0,
2.7]; 7.08 [2H, dt, CH ortho to OMe, J¼8.7, 2.6]; 7.28e
7.39 [5H, m, aromatics]. 13C NMR (75 MHz): ꢀ5.6, ꢀ5.5,
and ꢀ5.4 [2C, Si(CH3)2]; 17.8 [C(CH3)3]; 25.7 [3C,
SiC(CH3)3]; 26.2 (m), 27.0 (M ), 27.1 (M ), and 29.4 (m)
[2C, CH2 pyrrolidine]; 27.4 [3C, OC(CH3)3]; 33.2 (M ) and
33.7 (m) [NCOCH2]; 36.4 (m) and 36.7 (M ) [CH2NHZ];
55.2 [OCH3]; 59.2 (m) and 59.5 (M ) [CHCH2OSi]; 61.0
(M ) and 61.8 (m) [CHCONH]; 62.4 (m) and 63.1 (M )
[CH2OSi]; 65.1 [OCH2Ph]; 82.7 (M ) and 83.3 (m), 113.8
(M ) and 113.9 (m) [2C, CH ortho to OMe]; 127.6 and 127.9
[5C, CH of Ph]; 129.0 (M ) and 129.2 (m) [2C, CH meta to
OMe]; 130.8 (m) and 131.4 (M ) [C-NBoc]; 137.1 [C of Ph];
151.9 (m) and 152.3 (M ), 155.9, 158.2 (M ) and 158.4 (m)
[2C, C-OMe, CO (Z, Boc)]; 169.1 (M ) and 169.3 (m), 175.0
(m) and 175.6 (M ) [2C, CO].
4.17.2. Stereoisomer (7S,9aR) 61
Chromatography with CH2Cl2/Me2CO/MeOH 4:4:2 gave 60
as a white solid in 93% yield. Rf 0.34 (CH2Cl2/Me2CO/MeOH
4:4:2, B). Anal. Found: C, 54.65; H, 7.00; N, 14.00.
C9H14N2O3 requires C, 54.53; H, 7.12; N, 14.13. [a]2D0 þ8.3
(c 0.97, CHCl3/MeOH 9:1). Mp: 200.9e202.6 ꢁC (CH2Cl2/
Me2CO/MeOH). IR (KBr): nmax 3319, 3231, 2975, 1675,
1612, 1453, 1406, 1167, 1122, 1066, and 1045. GCeMS: tR
8.89; m/z 198 (Mþ, 3.7), 180 (7.5), 168 (26), 167 (100), 128
(6.2), 125 (27), 122 (9.2), 113 (22), 100 (22), 97 (22), 96 (9.5),
82 (9.0), 70 (6.6), 69 (11), 68 (56), 57 (6.7), 56 (7.5), 55 (23),
44 (6.8), 43 (8.1), 42 (8.0), 41 (17), 39 (7.4). 1H NMR
(300 MHz, DMSO-d6): 1.65e1.94 [3H, m, CH2CHH pyr-
rolidine]; 2.31e2.45 [2H, m, CH2CHH pyrrolidine,
CONHCH2CHH]; 2.64 [1H, ddd, CONHCH2CHH, J¼17.1,
5.1, 3.0]; 2.96e3.44 [3H, m, CONHCHHCH2, CH2O];
3.59[1H, center of m, CONHCHHCH2]; 4.11[1H, dt, CHCH2O,
J¼8.0, 3.6]; 4.65 [1H, dd, CHCONH, J¼9.3, 7.2]; 4.78 [1H, t,
OH, J¼5.7]; 7.96 [1H, br t, NH, J¼5.1]. 13C NMR (75 MHz):
24.1 and 25.1 [2C, CH2 pyrrolidine]; 35.9 [CONHCH2CH2];
36.6 [CONHCH2CH2]; 56.8 [CHCONHCH2]; 59.9 [CHCH2O];
60.3 [CH2O]; 168.9 and 170.8 [2C, CO].
4.17. TBDMS removal from 58 and 59
4.18. General procedure for oxidation to carboxylic acid
with PDC, followed by methyl ester or amide formation
A solution of 58 or 59 (150 mg, 48.00 mmol) in dry MeOH
(3 ml) was cooled to 0 ꢁC and then Amberlyst 15 (30 mg) was
added. After 30 min the reaction was allowed to stir at rt for
4 h. The mixture was diluted with CH2Cl2/Me2CO to solubi-
lize the product. Solid CaCO3 was added (z100 mg) and, af-
ter stirring for additional 15 min, a rapid filtration removed all
the solids. The solution was concentrated in vacuo and directly
purified by chromatography.
(a) Oxidation: a solution of alcohol 60 or 61 (100 mg,
50.45 mmol) in dry DMF (2 ml) was cooled to 0 ꢁC and then
pyridinium dichromate (PDC, 569 mg, 1.51 mmol) was added.
The resulting slurry was allowed to stir at rt for 20e26 h. After
dilution with 1e2 ml of CH2Cl2, solid Na2S2O5 was added
and, after 30 min, the mixture was directly filtered over a silica
column, using CH2Cl2/Me2CO 6:4/CH2Cl2/Me2CO/AcOH
3:6:1 as eluent. (b) Methyl ester: the general procedure
described in Section 4.13 was followed, but, due to insolubility
of the carboxylic acid in THF, DMF was employed. (c) Benzyl
amide formation: the carboxylic acid from the previous
reaction was partially solubilized in dry CH2Cl2/DMF
(2:1; 6 ml). After cooling to 0 ꢁC benzylamine (83 ml,
75.68 mmol), HATU [O-(7-azabenzotriazol-1-yl)-N,N,N0,N0-tet-
ramethyluronium hexafluorophosphate, 288 mg, 75.68 mmol],
and 2,4,6-collidine (113 ml, 85.77 mmol) were added and the
reaction was stirred at rt for 26 h. The solvents were
4.17.1. (7R,9aR)-Hexahydro-7-(hydroxymethyl)-2H-
pyrrolo[1,2-a][1,4]diazepine-1,5-dione 60
Chromatography with CH2Cl2/Me2CO/MeOH 4:4:2 gave 60
as a white solid in 93% yield. Rf 0.34 (CH2Cl2/Me2CO/MeOH
4:4:2, B). Anal. Found: C, 54.50; H, 7.15; N, 14.25.
C9H14N2O3 requires C, 54.53; H, 7.12; N, 14.13. [a]2D0 þ41.8
(c 0.97, CHCl3/MeOH 9:1). Mp: 178.5e180.1 ꢁC (CH2Cl2/
Me2CO/MeOH). IR (KBr): nmax 3379, 3257, 2937, 1679, 1610,
1452, 1409, 1168, 1116, and 1043. GCeMS: tR 8.30; m/z 198
(Mþ, 3.3), 180 (7.1), 168 (23), 167 (100), 139 (6.8), 128 (6.6),

L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
1133
evaporated under reduced pressure and the crude was directly
purified by chromatography.
Acknowledgements
The authors gratefully thank Mr. Andrea Galatini, Dr. Vale-
ria Rocca, and Dr. Carlo Scapolla for HPLC analysis, MUR
(PRIN04 and PRIN06), University of Genova, and Fondazione
S. Paolo for financial support.
4.18.1. (7R,9aR)-Methyl octahydro-1,5-dioxo-1H-pyrrolo-
[1,2-a][1,4]diazepine-7-carboxylate 62
Chromatography with CH2Cl2/MeOH 95:5/9:1 gave 62
as a pale yellow oil in 51% overall yield. Rf 0.36 (CH2Cl2/
MeOH 9:1, B). Anal. Found: C, 53.15; H, 6.30; N, 12.25.
C10H14N2O4 requires C, 53.09; H, 6.24; N, 12.38. [a]D20
þ69.5 (c 0.76). IR: nmax 3411, 2997, 1740, 1680, 1629,
1389, 1171, and 1111. GCeMS: tR 8.34; m/z 226 (Mþ, 38),
168 (10), 167 (100), 139 (6.1), 129 (6.5), 128 (86), 125
(20), 122 (7.3), 113 (18), 112 (5.3), 100 (5.0), 97 (17), 96
(11), 70 (5.1), 69 (15), 68 (87), 55 (15), 43 (5.3), 42 (8.4),
41 (24), 39 (7.4). 1H NMR (300 MHz, DMSO-d6): 1.78e
2.07 [3H, m, CH2CHH pyrrolidine]; 2.37e2.47 [2H, m,
CH2CHH pyrrolidine, CONHCH2CHH]; 2.72 [1H, dt, CON-
HCH2CHH, J¼18.0, 3.9]; 3.08 [1H, m, CONHCHHCH2];
3.63 [3H, s, OCH3]; 3.69 [1H, center of m, CONHCHHCH2];
4.44 [1H, dd, CHCO2Me, J¼7.8, 2.7]; 4.90 [1H, dd,
CHCONH, J¼8.1, 3.3]; 8.02 [1H, br t, NH, J¼5.1]. 13C
NMR (75 MHz): 25.8 and 26.5 [2C, CH2 pyrrolidine]; 35.6
[CONHCH2CH2]; 36.2 [CONHCH2CH2]; 51.8 [CH3]; 56.2
[CHCONHCH2]; 60.2 [CHCH2O]; 168.7, 170.7, and 172.0
[3C, CO].
References and notes
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7. Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley: Weinheim,
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4.18.2. Stereoisomer (7R,9aR) 63
9. Banfi, L.; Riva, R. Org. React. 2005, 65, 1e140.
´
10. Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.dEur. J. 2000, 6,
Chromatography with CH2Cl2/MeOH 95:5/9:1 gave 63 as
a pale yellow oil in 31% overall yield. Rf 0.31 (CH2Cl2/MeOH
9:1, B). Anal. Found: C, 53.00; H, 6.35; N, 12.40. C10H14N2O4
requires C, 53.09; H, 6.24; N, 12.38. [a]2D0 þ4.6 (c 0.68). IR:
nmax 3414, 3000, 1743, 1660, 1420, 1392, 1169, and 1077.
GCeMS: tR 8.31; m/z 226 (Mþ, 17), 168 (5.8), 167 (61), 129
(5.1), 128 (66), 125 (12), 113 (12), 112 (5.3), 100 (5.6), 97
(12), 96 (9.4), 70 (5.3), 69 (17), 68 (100), 67 (5.0), 56 (5.1),
3321e3329.
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¨
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1
55 (16), 44 (6.6), 43 (9.2), 42 (8.6), 40 (6.6), 39 (7.7). H
NMR (300 MHz, DMSO-d6): 1.80e2.14 [3H, m, CH2CHH
pyrrolidine]; 2.31e2.48 [2H, m, CH2CHH pyrrolidine,
CONHCH2CHH]; 2.67 [1H, ddd, CONHCH2CHH, J¼17.1,
7.8, 3.0]; 3.08 [1H, dq, CONHCHHCH2, J¼15.3, 5.1]; 3.60
[3H, s, OCH3]; 3.56e3.68 [1H, m, CONHCHHCH2]; 4.45
[1H, dd, CHCO2Me, J¼8.7, 3.0]; 4.74 [1H, t, CHCONH,
J¼7.6]; 8.05 [1H, br t, NH, J¼5.2]. 13C NMR (75 MHz): 26.3
and 26.5 [2C, CH2 pyrrolidine]; 35.6 [CONHCH2CH2]; 36.4
[CONHCH2CH2]; 51.8 [CH3]; 57.2 [CHCONHCH2]; 60.0
[CHCH2O]; 168.8, 170.1 and 171.8 [3C, CO].
13. Banfi, L.; Basso, A.; Guanti, G.; Kielland, N.; Repetto, C.; Riva, R. J. Org.
Chem. 2007, 72, 2151e2160.
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6637e6640.
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20. Pyrroline 13 is quite stable if stored at ꢀ25 ꢁC for about one month.
A prolonged storage requires indeed a chromatography to remove
by-products arising from a partial decomposition.
4.18.3. Compound 64¼34
Chromatography with CH2Cl2/MeOH 98:2/9:1 gave 64
in 61% overall yield. [a]2D0 þ37.3 (c 0.74, CH2Cl2/MeOH 9:1).
4.18.4. Compound 65¼ent-35
21. This was proved by NMR analysis of the diastereomeric Mosher’s esters
of 8. Later on the racemization was excluded in the whole sequence,
including also the Ugi reaction, as reported in Ref. 14.
Chromatography with CH2Cl2/MeOH 98:2/9:1 gave 64
in 73% overall yield. [a]2D0 þ28.1 (c 0.60, CH2Cl2/MeOH 9:1).

1134
L. Banfi et al. / Tetrahedron 64 (2008) 1114e1134
22. We preferred to isolate 13 and to perform the MCR as a separate step,
although recently an efficient one-pot Staudinger/aza-Wittig/Ugi reaction
on different sized cyclic imines has been reported (see: (a) Timmer,
M. S. M.; Risseeuw, M. D. P.; Verdoes, M.; Filippov, D. V.; Plaisier,
J. R.; van der Marel, G. A.; Overkleeft, H. S.; van Boom, J. H. Tetra-
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23. This isocyanide can also be conveniently prepared with higher degree of pu-
rity with respect to the commercial product through a two-step sequence,
transforming p-anisidine into the corresponding formamide (HCO2H,
DMF, CH2Cl2, rt, 95%) and submitting this intermediate to the usual dehy-
dration procedure (POCl3, Et3N, CH2Cl2, ꢀ30 ꢁC/0 ꢁC, 87%).
35. The procedure was first optimized on a compound similar to the one
described in Ref. 24 (only nBuNH2 was used instead of MeNH2 as amine
input to prepare it through the Ugi reaction) varying: (a) the base (tBuOK,
KHMDS, DBU, NaH, MeONa; (b) the temperature; (c) the work-up condi-
tions (quenching with NH4Cl, HCl, citric acid); (d) the terminal group of the
24. Lindhorst, T.; Bock, H.; Ugi, I. Tetrahedron 1999, 55, 7411e7420.
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literature procedure, submitting the formamide precursor to dehydration
with diphosgene, N-methylmorpholine, CH2Cl2, 0 ꢁC (88% yield).
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nucleophiles such as alcohols. For example, when purified by chroma-
tography with an eluent containing methanol, a partial conversion into
the open methyl ester was observed.
i
t
carbonate (Me, Bu, Bu). No improvement was noticed when iso-butyl
carbonatewas used. When tert-butyl carbonatewas employed always a mix-
ture of products was obtained, the major one being the primary alcohol,
followed by the acyl oxazolidinone and, finally, by the desired methyl ester.
36. Under the same conditions model compound of Ref. 35 gave exclusively
the desired methyl ester.
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substitute NaHSO3, as reducing agent, with a little amount of methanol:
otherwise the following hydrogenolysis did not occur.
39. Racemization did not occur during the preparation of the isocyanide, pro-
vided that dehydration of its precursor (the formamide) is performed with
diphosgene and not with POCl3. The stereochemical problem lies exclu-
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Passerini reaction, employing the same components but in the absence of
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~
´
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