A new convergent and stereoselective synthesis of 2,5-disubstituted N-acylpyrrolidines

Article abstract of DOI:10.1016/j.tet.2006.02.073

A new synthesis of 2,5-disubstituted N-acylpyrrolidines through an S_N2′ reaction promoted by the nitrogen anion of a secondary amide onto an allylic bromide is reported. A moderate stereoselectivity, in favour of the trans heterocycle, was obse

Full text of DOI:10.1016/j.tet.2006.02.073

Tetrahedron 62 (2006) 4331–4341
A new convergent and stereoselective synthesis
of 2,5-disubstituted N-acylpyrrolidines
*
Luca Banfi, Andrea Basso, Giuseppe Guanti and Renata Riva
Dipartimento di Chimica e Chimica Industriale, Via Dodecaneso 31, I-16146 Genova, Italy
Received 7 December 2005; revised 9 February 2006; accepted 23 February 2006
Abstract—A new synthesis of 2,5-disubstituted N-acylpyrrolidines through an SN20 reaction promoted by the nitrogen anion of a secondary
amide onto an allylic bromide is reported. A moderate stereoselectivity, in favour of the trans heterocycle, was observed during the
cyclization of a chiral precursor, while a good stereoselectivity, this time in favour of the cis one, was obtained when the second stereocentre
was introduced after the cyclization step to give the same product.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In our project, we planned to synthesise a series of [n,3,0]
bicyclic scaffolds such as 1 (Scheme 1) and, in view of
cyclization through RCM as the final step, we would need a
convergent synthesis of N-acyl-2-carbalkoxy-5-vinylpyrro-
lidines 2. An attractive strategy towards this goal involves
an SN20 procedure promoted by a nitrogen nucleophile onto
a double bond equipped with a suitable leaving group at the
terminal allylic position. The acyclic precursor 3 may be
assembled, for example, by alkylation of a-acylaminoesters
or malonates 4. Malonates can be used in place of simple
esters; thanks to the possibility of removing the second
carbalkoxy group via saponification–decarboxylation. This
step can be performed either before or after cyclization.
Moreover, for an efficient and convergent approach to 1, R3
group should be equipped with both the double bond, to be
used in RCM, and NHR1 group essential, together with
Pyrrolidine is a very important heterocycle present in many
biologically active compounds, such as proteins or alkaloids
and has become one of the priviledged structures in drug
discovery.1 In particular, bicyclic lactams, bearing a
pyrrolidine moiety and equipped with suitable appendages,
are very popular since they can be used as constrained
peptidomimetics.2 Moreover, they are frequently able to
mimic a reverse turn, an important motif responsible for
inducing the appropriate conformation in small oligo-
peptides involved in essential interactions with many
biological targets. An example is represented by bicyclic
lactams included in a macrocycle together with the RGD
sequence: in this case, the bicyclic system acts as an
‘external scaffold’3 and these molecules showed interesting
properties as inhibitors of aVb3 or aVb5 integrins.4 In the
last few years, our group has been involved in the synthesis
of either mesocyclic lactams5,6 or bicyclic derivatives7 as
possible inhibitors of integrins.
via RCM
O
2
CO R
2
N
N
1
Arg
Gly
NHR
m
O
The previous reported synthesis of [n,3,0] (nZ4, 5, 6, 7)
bicyclic systems are based on the construction of the larger
ring as the last step, employing usually the highly versatile
ring closing metathesis (RCM),8 but standard lactonization7
or lactamization reactions9 or radical cyclizations10 have
been utilized too. Therefore, in the first part of these
syntheses, a suitably functionalized pyrrolidine had to be
assembled.
O
3
= R
NH
m -1
1
2
Asp
X
via S 2'
N
4
4
2
O
R
R = H or CO R
O
4
2
R
3
2
3
2
R
NH CO R
R
NH CO R
2
2
Keywords: Pyrrolidine; SN20; Peptidomimetics.
4
3
*
Corresponding author. Tel.:C39 0103536126; fax: C39 0103536118;
e-mail: riva@chimica.unige.it
Scheme 1.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.073

4332
L. Banfi et al. / Tetrahedron 62 (2006) 4331–4341
CO2R2, for the creation of the macrocyclic peptidic
structure including for example RGD motif.
a, 94%
OH
OPMB
7
b, 85%
To the best of our knowledge, intramolecular SN20 reactions,
starting from simple secondary amides, were unprecedented.
While in a few cases pyrrolidines or piperidines have been
prepared through an SN20 cyclizations under palladium
catalysis,11 those examples involved the use of carbamates.
Thus, the success of the envisaged strategy was not obvious,
since it is known that in amides there is often a competition
between N and O-alkylation, affording, in our case, 5 or 6,
respectively, as outlined in Scheme 2.12 In carbamates this
competition is less important. The development of a protocol
leading in one-pot to N-acyl derivatives (and not to
carbamates) would considerably shorten the approach to key
intermediate 2 (that may be in principle obtained also through
a Ugi multicomponent reaction). The feasibility of our
hypothesis was studied on a model compound, that is the
acetamide corresponding to general formula 3 (R3 ZMe).13
HO
c, 91%
HO
OPMB
OPMB
9
8
d, 96%
e,
82%
TBDPSO
OPMB
TBDPSO
TBDPSO
OH
10
11
f
g, 83%
TBDPSO
Br
OTs
13
12
Scheme 3. (a) NaH, p-methoxybenzylchloride, DMF, 0 8C; (b) (i) EtMgBr,
paraformaldehyde, THF, rt; (ii) K2CO3, MeOH, rt; (c) LiAlH4, MeONa,
THF, reflux; (d) Ph2tBuSiCl, imidazole, DMF, rt; (e) DDQ, CH2Cl2/H2O
20:1, rt; (f) TsCl, py, rt; (g) KBr, DMF, 100 8C.
X
13 in excellent overall yield, provided that tosylate 12 is
recovered by neutral work-up and submitted immediately
to nucleophilic displacement without previous purification.
Despite the long preparation, the overall yield of this
bromide from 3-butyn-1-ol was a remarkable 48%.
O
4
N-cyclization
O-cyclization
2
R
3
R
NH CO R
2
3
The alkylation of diethyl acetamido malonate was found to
be troublesome, most likely because of the propensity of the
rather unreactive bromide 13 to undergo competitive
reactions, such as elimination, to give the corresponding
4
R
4
R
2
CO R
2
2
N
CO R
2
O
N
3
5
6
R
O
3
R
OTBDPS
Scheme 2.
2. Results and discussion
CO Et
2
a, 75-88%
b, 83%
CO Et
2
N-Acetyl homoallylglycinates are not available commer-
cially either in racemic or in enantiopure form; thus we had
to develop a convergent racemic synthesis of them,
involving the alkylation of the enolate of unexpensive
diethyl acetamido malonate with a suitable homoallylic
bromide, equipped with a masked leaving group at the
allylic position to be exploited in the cyclization.
AcNH
AcNH
AcNH
CO Et
AcNH
CO Et
2
2
14
d, 85%
(19)
OTBDPS
OH
1
d, 96% (17)
R
The initial task was therefore the preparation of a 2-pentene
substituted at position 5 (a homoallylic carbon) with a good
leaving group and at the more reactive position 1 (an allylic
carbon), with a poor one. We started from commercially
available 3-butyn-1-ol (Scheme 3), that was protected as
p-methoxybenzyl ether (PMB) and then homologated
by treatment of the magnesium acetylide of 7 with
paraformaldehyde. Compound 8, obtained in excellent
yield after hydrolysis under basic conditions of the complex
mixture of hemiacetalic derivatives of formaldehyde,14
contained two differentiated primary alcoholic functional-
ities, that have been elaborated independently during the
synthesis.15 The free propargylic alcohol was reduced to
give, with total control of the geometry of the incoming
double bond, allylic alcohol 9 in excellent yield.16 Silylation
of 9 allowed to prepare 10, with two orthogonally protected
hydroxy groups. Removal of PMB under oxidative
conditions afforded 11, ready to be converted into bromide
2
CO Et
AcNH
CO R
2
2
15
17,18,19
e,
d, 80%
c, 75%
66% (20),
f,
(18)
OTBDPS
X
88% (21),
75% (22),
92% (23),
1
R
2
CO tBu
AcNH
CO R
2
2
16
20,21,22,23
1
2
1
2
1
2
17: R = H, R = Et; 18: R = H, R = tBu; 19: R = CO Et, R = Et
2
1
2
1
2
20: R = H, R = Et, X = Cl; 21: R = H, R = Et, X = Br;
1
2
1
2
22: R = H, R = tBu, X = Br; 23: R = CO Et, R = Et, X = Br
2
Scheme 4. (a) NaH, 13, DMF, 90 8C; (b) (i) NaOH 6 M in EtOH, EtOH,
rt; (ii) HC; (iii) dioxane, reflux; (c) (i) NaOH 6 N, EtOH, rt; (ii)
CCl3C(]NH)OtBu, BF3$Et2O, CH2Cl2, rt; (d) nBu4NF, THF, rt; (e) CCl4,
PPh3, reflux; (f) CBr4, PPh3, CH3CN, rt.

L. Banfi et al. / Tetrahedron 62 (2006) 4331–4341
4333
conjugated diene. After a careful optimization of the
conditions we succeeded in obtaining 14 in good yield
(Scheme 4).17
tivity in favour of the trans stereoisomer 24a was observed
(entry 1, Table 1).20 Under the same conditions, bromide 21
showed to be, as expected, more reactive, affording 24a,b in
higher yield, but with similar diastereoselectivity (entry 2).
The following screening was therefore done on the best
performing substrate 21. Other bases, such as NaH gave
unsatisfactory results (entry 5), particularly from the
stereochemical point of view, while an improved diastereo-
meric ratio was observed using the lithium anion
of bis(trimethylsilyl)amide (LiHMDS).21 The reaction
temperature showed an appreciable influence just on the
rate, but not on the stereoselectivity. Also the nature of the
solvent was varied, demonstrating that optimal results can
be achieved with the aprotic dipolar ones. Interestingly,
when apolar toluene was used (entry 7) a reversal of
stereoselectivity was observed. However, this reaction was
too slow for preparative purposes. Compounds 24a,b
showed to be configurationally stable under basic
conditions, since no changes in diastereomeric ratio were
observed after prolonged storage under the reaction
conditions.
Monodecarboxylation, following our protocol developed for
structurally similar compounds, afforded finally 15.6 As the
final step, we studied the transformation of the silyl ether into
a halide, via the free alcohol 17. When we tried to prepare the
tosylate,18 we could not isolate it, but it was readily converted
into the corresponding chloride 20, albeit in unsatisfactory
yield. For this reason, we used a direct method, which
employed triphenyl phosphine and carbon tetrachloride both
as reagent and solvent.19 Although harsher conditions than the
reported ones were required, chloride 20 was finally isolated
in acceptable yield. Modified reaction conditions, using
carbon tetrabromide and triphenylphosphine in acetonitrile,
allowed the preparation of bromide 21 in higher yield and
under milder conditions.
During the first cyclization experiment (Scheme 5) we
treated chloride 20 with potassium bis(trimethylsilyl)amide
(KHMDS) and we were pleased to discover the only
products derived from N-promoted cyclization. The yield
was, however, moderate, whereas a poor diastereoselec-
The bulkier t-butyl ester 22 was obtained from 15 by a three
step procedure (Scheme 4). Its cyclization was slower and
required a temperature of at least K50 8C in order to start,
while no improvement in the diastereomeric ratio was
realized (entry 11).
X
In order to improve the stereoselectivity and gain access to the
minor cis diastereoisomer, we carried out the cyclization also
starting from malonate 23 (entry 12). The reaction took place
in good yield to give 26. This reaction is particularly
interesting since the monodecarboxylation of 26 affords
24a,b with good stereoselectivity favouring this time the cis
diastereoisomer24bina7.3:1ratio.Thus,twocomplementary
procedures affording prevailingly either 24a or 24b are
available and, since the two diastereoisomers can be separated
although not easily by chromatography, our protocol
constitutes an original new entry for the stereoselective
synthesis of vinyl-substituted N-heterocycles.
R1
CO2R2
a (from 20, 21 or 22)
AcNH
20,21,22,23
CO2R2
N
CO2R2
+
N
a (from 23)
24,25a
24,25b
O
O
b, 80%
CO2Et
CO2Et
N
12:88 24a : 24b
O
26
24a,b: R2=Et; 25a, b: R2=tBu
Scheme 5. (a) see Table 1; (b) (i) NaOH 6 N, EtOH; (ii) HC; (iii) dioxane,
reflux.
The determination of the relative configuration of 24a and
24b was first done tentatively by 1H NMR correlation with
Table 1. Cyclization of halides 20–23, through SN20 reaction
Entry
Halide
Basea
Solventb
Temperature (8C)
Time (h)
Product(s)
Yield (%)c
drd
1
2
3
4
5
6
7
8
20
21
21
21
21
21
21
21
21
21
22
23
KHMDSe
KHMDSe
LiHMDSf
LiHMDSf
NaH
THF/DMF 2:1
THF/DMF 2:1
THF/DMF 2:1
THF/DMF 2:1
THF/DMF 2:1
THF
K108/rt
K108/08
K108
K788/K58
K108
K108/rt
K108/rt
K108/rt
K108/rt
K788
3.5
0.67
4
24
2
46
50
4.25
6
25
22
2.5
24a,b
24a,b
24a,b
24a,b
24a,b
24a,b
24a,b
24a,b
24a,b
24a,b
25a,b
26
50
80
81
74
68
55
75
80
81
90
75
78
56:44
55:45
54:46
67:33
51:49
58:42
38:62
70:30
63:37
70:30
69:31
—
LiHMDSf
LiHMDSf
LiHMDSf
LiHMDSf
LiHMDSf
LiHMDSf
LiHMDSg
Toluene
THF/DMSO 3:1
DMF
DMF
DMF
DMF
9
10
11
12
K788/K508
K158/88
a 1.5 mol equiv of base.
b 0.05–0.07 M with respect to substrate, with the exception of DMF (0.25 M).
c In entries 1–11 the yield is referred to the diastereomeric mixture.
d By GC–MS.
e KHMDS: potassium bis(trimethylsilyl)amide, 0.5 M solution in THF freshly prepared by dissolving solid commercial KHMDS.
f
LiHMDS: lithium bis(trimethylsilyl)amide, 1.0 M commercial solution in THF.
g LiHMDS: 0.5 M solution in THF freshly prepared by dissolving solid commercial LiHMDS.

4334
L. Banfi et al. / Tetrahedron 62 (2006) 4331–4341
similar compounds.22 In particular, while in the trans
derivatives the chemical shifts of the terminal vinylic
protons are close together, in the cis series a 0.24–0.28 ppm
difference was always observed, with the proton trans to the
other vinylic one downfield. Moreover, our expectations
were confirmed by transforming both stereoisomers into
triacetyl derivatives 29a,b (Scheme 6).23 After chemo-
selective reduction of the ester with Ca(BH4)2 and
acetylation of the primary alcohol, acetates 28a,b were
submitted to ozonolysis and acetylation of the crude
product24 to give, in excellent yield, desired 29a,b. Since
24a and 24b are racemic, we reasoned that a different
behaviour could, in principle, be observed if 29a and 29b
are put in a chiral medium, because the first one is racemic
and the second one is a meso compound. Chiral GLC, using
two different functionalized b-cyclodextrin-based columns,
always gave one peak for both 29a and 29b. On the
contrary, HPLC with a Chiralpak AD column, gave an
excellent separation, with two peaks eluting with Rt 15.92
and 17.41 min, respectively (see Section 4), for the triacyl
compou0nd derived from the major stereoisomer obtained in
the SN2 cyclization. Using the same conditions, the other
diastereoisomer eluted as a single peak at Rt 12.65 min.
Since, during the transformation of 24a and 24b into 29a
and 29b, the original stereogenic centres were not subjected
to manipulations, the behaviour in HPLC allows us to assign
the trans stereochemistry to the prevailing stereoisomer
obtained in the SN20 cyclization and the cis stereochemistry
to the prevailing stereoisomer obtained in the
monodecarboxylation of 26.
progress in our laboratory and will be presented in due
course.
4. Experimental
4.1. General
NMR spectra were taken in CDCl3 at 200 or 300 MHz (1H)
and 50 or 75 MHz (13C), using TMS as internal standard.
Chemical shifts are reported in ppm (d scale), coupling
constants are reported in hertz. Peak assignment in 1H NMR
spectra was also made with the aid of double resonance
experiments. Peak assignment in 13C spectra was made with
the aid of DEPT experiments. GC–MS 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
temperature of about 170 8C. Unless otherwise indicated,
analyses were performed with a constant He flow of
0.9 ml/min, init. temperature 100 8C, init. time 2 min, rate
20 8C/min, final temperature 260 8C, final time 4 min, inj.
temperature 250 8C, det. temperature 280 8C. Rt are in min.
HPLC determinations were carried out on a HP-1090
instrument equipped with a DAD detector and using a
Chiralpak AD column (25 cm long, 0.4 cm wide). IR spectra
were measured with a Perkin–Elmer 881 instrument as
CHCl3 solutions. Melting points were determined on a
Bu¨chi 535 apparatus and are uncorrected. 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. Rf were measured after an elution of 7–9 cm.
Chromatographies were carried out on 220–400 mesh
silica gel using the ‘flash’ methodology. Petroleum ether
(40–60 8C) is abbreviated as PE. In extractive work-up,
aqueous solutions were always reextracted thrice with the
appropriate organic solvent. Organic extracts were washed
with brine, dried over Na2SO4 and filtered, before
evaporation of the solvent under reduced pressure. All
reactions employing dry solvents were carried out under a
nitrogen atmosphere, while SN20 reactions were performed
under ultra pure argon.
a, 89%
CO Et
2
N
N
OH
O
O
24a,b
27a,b
b, 90% or 82%
from 24a,b
c, 80%
N
N
AcO
OAc
OAc
O
O
29a,b
28a,b
a: 2,5-trans; b; 2,5-cis
Scheme 6. (a) Ca(BH4)2, THF/EtOH 2:1, K20 8C; (b) Ac2O, Et3N,
4-(dimethylamino)pyridine, CH2Cl2, rt; (c) CH2Cl2/MeOH 1:1, K78 8C;
(ii) NaBH4 K78 8C/rt; (iii) see (b).
4.2. 4-(4-Methoxybenzyl)oxybut-1-yne 7
To a solution of 4-methoxybenzyl chloride (7.89 g,
50.4 mmol) in dry DMF (50 ml) previously cooled in an
ice bath, 3-butyn-1-ol (3.47 ml, 45.8 mmol) was added via
syringe. NaH (2.02 g, 60% in mineral oil, 50.4 mmol) was
added portionwise over a period of 15 min and the resulting
slurry was stirred at 0 8C for additional 45 min. After adding
NH4Cl satd soln (20 ml), the mixture was partitioned
between water and Et2O and extracted. Chromatography
with PE/Et2O 9:1/8:2 gave 7 (8.19 g, 94%) as a colourless
oil. Rf 0.32 (PE/Et2O 9:1, A, C). Anal. found C, 75.50; H,
7.40. C12H14O2 requires C, 75.76; H, 7.42. IR: nmax 3305,
2965, 2397, 1611, 1243, 1172, 1091, 1031. GC–MS: Rt
5.26; m/z 190 (MC, 7.8), 189 (13), 159 (11), 135 (25), 122
(9.6), 121 (100), 91 (7.2), 78 (14), 77 (16), 53 (9.2), 52 (5.6),
3. Conclusions
In this paper, we presented a new high convergent protocol
for the synthesis of functionalized N-heterocycles that can
be further elaborated to more complex structures. Moreover,
our methodology could probably be extended for the
synthesis of differently sized rings and of different
N-acylated compounds.
The development of different convergent strategies for the
preparation of acyclic precursors 3, involving, for example,
an approach based on multicomponent reactions, may
disclose a new way for the synthesis of polycyclic
derivatives, through methodologies consistent with diver-
sity oriented synthesis.25 Studies in this field are still in
1
51 (8.0), 39 (10). H NMR (200 MHz): 1.99 [1H, t, ^CH,
JZ2.6 Hz]; 2.49 [2H, dt, CH2C^, JZ2.6, 7.0 Hz]; 3.57
[2H, t, CH2CH2O, JZ7.1 Hz]; 3.81 [3H, s, OCH3]; 4.49

L. Banfi et al. / Tetrahedron 62 (2006) 4331–4341
4335
[2H, s, CH2Ar]; 6.88 [2H, dt, aromatics ortho to OMe, JZ
2.4, 8.8 Hz]; 7.28 [2H, d, aromatics meta to OMe, JZ
8.8 Hz]. 13C NMR (50 MHz): 19.80 [CH2C^]; 55.17
[CH3O]; 67.75 [CH2CH2O]; 69.25 [^CH]; 72.55
[CH2Ar]; 81.28 [C^CH]; 113.72 [2C, aromatics ortho to
OMe]; 129.26 [2C, aromatics meta to OMe]; 130.00 [quat.
aromatic]; 159.17 [C–OMe].
8.25. C13H18O3 requires C, 70.24; H, 8.16. IR: nmax 3462,
2998, 2929, 2864, 1609, 1533, 1419, 1364, 1190, 1088, 972.
GC–MS: Rt 7.28; m/z 222 (MC, 1.0), 150 (10), 137 (6.4),
136 (8.3), 135 (7.2), 122 (10), 121 (100), 78 (8.2), 77 (9.6).
1H NMR (200 MHz): 1.37 [1H, t, OH, JZ5.9 Hz]; 2.36
[2H, centre of m, CH2CH2CZ]; 3.49 [2H, t, CH2CH2O, JZ
6.6 Hz]; 3.81 [3H, s, OCH3]; 4.09 [2H, broad s, CH2OH];
4.44 [2H, s, CH2Ar]; 5.62–5.81 [2H, m, CH]CH]; 6.88
[2H, dt, aromatics ortho to OMe, JZ2.4, 8.8 Hz]; 7.26 [2H,
d, aromatics meta to OMe, JZ8.8 Hz]. 13C NMR (50 MHz):
32.53 [CH2CH2CH]]; 55.17 [CH3O]; 63.33 [CH2OH];
69.23 [CH2CH2O]; 72.44 [CH2Ar]; 113.70 [2C, aromatics
ortho to OMe]; 128.96 and 130.98 [2C, CH]CH]; 129.24
[2C, aromatics meta to OMe]; 130.29 [quat. aromatic];
159.09 [C–OMe].
4.3. 5-[(4-Methoxybenzyl)oxy]pent-2-yn-1-ol 8
A solution of 7 (7.22 g, 38.0 mmol) in dry THF (100 ml)
was cooled to 0 8C and then EtMgBr (3 M soln in Et2O,
21.5 ml) was dropped via syringe over a period of 2–3 min.
After 10 min, the cooling bath was removed and stirring
continued at rt for 30 min. Anhydrous paraformaldehyde
(8.11 g, 271 mmol) was then added in one-pot and the
resulting suspension was stirred at rt for 1 day. Quenching
with NH4Cl satd soln (70 ml) was followed by stirring at rt
for 15 min; then the crude was filtered through a Celite pad,
washing Celite with Et2O and AcOEt. After separation of
the two layers two additional extractions with Et2O were
performed. Solvent was removed and the crude was
dissolved in MeOH (40 ml) and stirred at rt in the presence
of anhydrous K2CO3 (1.00 g, 7.24 mmol) for 3 h. After
filtration of the solid and solvent evaporation, the residue
was partitioned between H2O and AcOEt and extracted with
AcOEt. Chromatography with PE/Et2O 4:6/1:9 gave 8
(7.11 g, 85%) as a colourless oil. Rf 0.44 (PE/Et2O 3:7,
A, C). Anal. found C, 70.75; H, 7.35. C13H16O3 requires C,
70.89; H, 7.32. IR: nmax 3401, 3003, 2416, 1612, 1506,
1300, 1172, 1087, 924. GC–MS: Rt 7.52; m/z 220 (MC,
0.70), 201 (6.3), 189 (20), 171 (9.2), 135 (10), 122 (9.7), 121
(100), 91 (6.5), 78 (13), 77 (14), 65 (6.5), 51 (6.4), 39 (10).
1H NMR (200 MHz): 1.72 [1H, t, OH, JZ6.0 Hz]; 2.52
[2H, tt, CH2CH2C^, JZ2.2, 7.0 Hz]; 3.55 [2H, t,
CH2CH2O, JZ6.9 Hz]; 3.81 [3H, s, OCH3]; 4.24 [2H,
broad dt, CH2OH, JZ2.1, 5.8 Hz]; 4.48 [2H, s, CH2Ar];
6.88 [2H, dt, aromatics ortho to OMe, JZ2.4, 8.4 Hz]; 7.27
[2H, d, aromatics meta to OMe, JZ8.8 Hz]. 13C NMR
(50 MHz): 19.99 [CH2CH2C^]; 50.91 [CH2OH]; 55.15
[CH3O]; 67.80 [CH2CH2O]; 72.44 [CH2Ar]; 79.56 and
82.69 [2C, C^C]; 113.71 [2C, aromatics ortho to OMe];
129.28 [2C, aromatics meta to OMe]; 129.85 [quat.
aromatic]; 159.15 [C–OMe].
4.5. (E)-1-[(t-Butyldiphenylsilyl)oxy-5-(4-methoxy-
benzyl)oxy]pent-2-ene 10
A solution of 9 (5.60 g, 25.2 mmol) in dry DMF (40 ml) was
cooled to 0 8C and treated with imidazole (3.09 g,
45.3 mmol) and Ph2tBuSiCl (8.52 ml, 32.8 mmol). After
5 min, the solution was allowed to stir at rt for 3.5 h. The
reaction was diluted with PE/Et2O 1:1 and water and
extracted with PE/Et2O. Chromatography with PE/Et2O
92:8/85:15 gave 10 as a pale yellow oil (11.14 g, 96%). Rf
0.33 (PE/Et2O 9:1, A, C). Anal. found C, 75.70; H, 7.85.
C29H36O3Si requires C, 75.61; H, 7.88. IR: nmax 3465, 3001,
2931, 2856, 1610, 1506, 1190, 1109, 1031, 969. GC–MS
(usual method but with final temperature 290 8C): Rt 12.89;
m/z 403 (MCK57, 0.30), 199 (2.9), 197 (1.5), 183 (1.1), 181
(1.1), 135 (2.2), 123 (1.0), 122 (9.9), 121 (100), 105 (1.1), 91
1
(1.4), 78 (1.7), 77 (3.2). H NMR (200 MHz): 1.05 [9H, s,
tBu]; 2.34 [2H, centre of m, CH2CH2C]]; 3.46 [2H, t,
CH2CH2O, JZ6.8 Hz]; 3.80 [3H, s, OCH3]; 4.16 [2H,
apparent d, CH2OTBDPS, JZ3.2 Hz]; 4.44 [2H, s, CH2Ar];
5.55–5.77 [2H, m, CHZCH]; 6.86 [2H, dt, aromatics ortho
to OMe, JZ2.4, 8.8 Hz]; 7.23–7.46 [8H, m, aromatics];
7.65–7.73 [4H, m, aromatics]. 13C NMR (50 MHz): 19.21
[C(CH3)3]; 26.86 [3C, C(CH3)3]; 32.71 [CH2CH2CH]];
55.22 [CH3O]; 64.48 [CH2OTBDPS]; 69.57 [CH2CH2O];
72.54 [CH2Ar]; 113.75 [2C, aromatics ortho to OMe];
127.26 and 130.68 [2C, CH]CH]; 127.59 [4C, aromatics
meta to Si]; 129.21 [2C, aromatics meta to OMe]; 129.55
[2C, aromatics para to Si]; 130.59 [quat. aromatic para to
OMe]; 133.84 [2C, C ipso of Ph]; 135.54 [4C, aromatics
ortho to Si]; 159.13 [C–OMe].
4.4. (E)-5-[(4-Methoxybenzyl)oxy]pent-2-en-1-ol 9
A suspension of LiAlH4 (3.16 g, 83.2 mmol) in dry THF
(120 ml) was cooled to 0 8C and sodium methoxide (8.07 g,
166 mmol) was added. A solution of 8 (6.11 g, 27.7 mmol)
in dry THF (30 ml) was dropped through an addition funnel
over a period of 15 min and the cooling bath was removed
after 5 min. The funnel was substituted with a refrigerator
and the mixture was refluxed for 5 h 15 min. After cooling
the flask at 0 8C, a solution of NaOH (370 mg in 12.5 ml of
water) was added wery slowly and the mixture was stirred
overnight at rt. The white solid was readily filtered and
washed with Et2O. The collected organic layers were dryed
over Na2SO4 and evaporated to give a yellow oil, pure
enough (GC–MS) for the following reaction. For analytical
purposes the crude was purified by chromatography with
PE/Et2O 1:1/2:8 to give 9 as a pale yellow oil in 91%
yield. Rf 0.31 (PE/Et2O 3:7, A, C). Anal. found C, 70.40; H,
4.6. (E)-5-[(t-Butyldiphenylsilyl)oxy]pent-3-en-1-ol 11
A solution of 10 (8.31 g, 18.0 mmol) in CH2Cl2 (50 ml) was
cooled to 0 8C and treated with water (2.5 ml) and DDQ
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (6.14 g,
27.1 mmol). After 5 min the solution was allowed to stir
at rt for 1 h 10 min. The mixture was partitioned between
5% NaHCO3 and CH2Cl2 and filtered over a Celite pad. The
filtrate was extracted again with CH2Cl2. Chromatography
with PE/Et2O 6:4 gave 11 as a colourless oil (5.04 g, 82%).
Rf 0.26 (PE/Et2O 6:4, A, C). Anal. found C, 74.15; H, 8.25.
C21H28O2Si requires C, 74.07; H, 8.29. IR: nmax 3464, 3006,
2927, 2857, 1680, 1598, 1243, 1108, 1029, 927. GC–MS: Rt
9.52; m/z 283 (MCK57, 15), 253 (14), 205 (27), 201 (5.2),
200 (19), 199 (100), 197 (9.8), 187 (5.1), 181 (10), 175 (18),

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L. Banfi et al. / Tetrahedron 62 (2006) 4331–4341
174 (5.2), 139 (17), 135 (7.7), 127 (5.2), 121 (6.4), 105 (8.3),
78 (5.4), 77 (22), 67 (6.9), 57 (5.2), 45 (14), 41 (12), 39
(5.7). H NMR (200 MHz): 1.06 [9H, s, tBu]; 2.29 [2H,
4.19 [2H, m, CH2OTBDPS]; 5.65–5.70 [2H, m, CH]CH];
7.33–7.47 [6H, m, aromatics]; 7.66–7.72 [4H, m,
aromatics]. 13C NMR (50 MHz): 19.22 [C(CH3)3]; 26.83
[3C, C(CH3)3]; 32.31 [CH2CH2CH]]; 35.57 [CH2Br];
64.10 [CH2OTBDPS]; 126.94 and 131.91 [2C, CH]CH];
127.64 [4C, aromatics meta to Si]; 129.63 [2C, aromatics
para to Si]; 133.68 [2C, C ipso of Ph]; 135.54 [4C,
aromatics ortho to Si].
1
broad q, CH2CH2CZ, JZ6.0 Hz]; 3.63 [2H, t, CH2CH2OH,
JZ6.0 Hz]; 4.19 [2H, apparent d, CH2OTBDPS,
JZ3.0 Hz]; 5.54–5.75 [2H, m, CH]CH]; 7.33–7.47
[6H, m, aromatics]; 7.66–7.71 [4H, m, aromatics]. 13C
NMR (50 MHz): 19.22 [C(CH3)3]; 26.85 [3C, C(CH3)3];
35.62 [CH2CH2CH]]; 61.85 [CH2OH]; 64.33 [CH2-
OTBDPS]; 126.58 and 132.22 [2C, CH]CH]; 127.65
[4C, aromatics meta to Si]; 129.65 [2C, aromatics para to
Si]; 133.75 [2C, C ipso of Ph]; 135.56 [4C, aromatics ortho
to Si].
4.8. (E)-Diethyl 2-acetamido-2-{5-[(t-butyldiphenyl-
silyl)oxy]pent-3-enyl}malonate 14
A suspension of NaH (60% in mineral oil, 388 mg,
9.70 mmol) in dry DMF (10 ml) was cooled to 0 8C. Then
a
solution of diethyl acetamidomalonate (2.33 g,
4.7. (E)-5-Bromo-1-[(t-butyldiphenylsilyl)oxy]pent-2-
ene 13
10.7 mmol) in DMF (10 ml) was added through an addition
funnel over a period of 10 min. After stirring for additional
5 min at rt, the resulting yellow solution was treated with a
solution of bromide 13 (2.94 g, 7.29 mmol) in DMF (10 ml)
and immediately heated at 90 8C for 3 h. After this time, the
reaction was quenched, even if some unreacted bromide was
still present. The resulting solution was cautiously added to
saturated aqueous NH4Cl, diluted with water and extracted
with Et2O. Chromatography with PE/Et2O 8:2/2:8
afforded pure 14 in 75–88% yield as a pale yellow oil. Rf
0.51 (PE/AcOEt 6:4, A, B). Anal. found C, 66.80; H, 7.60.
C30H41NO6Si requires C, 66.76; H, 7.66. IR: nmax 3411,
2998, 2957, 2856, 1736, 1675, 1187, 1105, 1032, 922.
GC–MS (usual method but with final temperature 290 8C):
Rt 13.32; m/z 483 (15), 482 (MCK57, 44), 260 (8.9), 238
(6.0), 201 (5.6), 200 (18), 199 (100), 197 (20), 183 (12), 181
(14), 178 (11), 174 (6.5), 173 (7.3), 169 (8.3), 168 (72), 167
(7.6), 140 (10), 139 (16), 137 (6.6), 135 (20), 123 (9.6), 122
(7.5), 121 (8.6), 105 (10), 95 (5.2), 94 (21), 79 (7.2), 77 (83),
(1) Tosylate 12. A solution of 11 (2.52 g, 7.42 mmol) in dry
pyridine (7 ml) was treated at 0 8C with freshly distilled
tosyl chloride (1.98 g, 10.4 mmol) and, after 5 min, allowed
to stir at rt for 1 h 45 min (in some cases an addition of
0.4 mol equiv of tosyl chloride was required). The solution
was poured into water and extracted with AcOEt. Solvent
was removed under vacuo employing also heptane to
remove azeotropically residue pyridine and crude tosylate
was directly submitted to the nucleophilic displacement. For
analytical purposes a sample of the crude was chromato-
graphed with PE/Et2O 9:1/6:4 to give 12 as a pale yellow
oil. Rf 0.63 (PE/Et2O 6:4, A, C). IR: nmax 3004, 2932, 2855,
1
1599, 1360, 1191, 1110, 969. GC–MS: not feasible. H
NMR (200 MHz): 1.04 [9H, s, tBu]; 2.27–2.40 [2H, m,
CH2CH2C]]; 2.42 [3H, s, CH3 (Ts)]; 4.02 [2H, t, CH2OTs,
JZ6.8 Hz]; 4.11 [2H, apparent d, CH2OTBDPS, JZ
3.0 Hz]; 5.45–5.68 [2H, m, CH]CH]; 7.29–7.45 [8H, m,
aromatics]; 7.62–7.80 [6H, m, aromatics]. 13C NMR
(50 MHz): 19.20 [C(CH3)3]; 21.61 [CH3 (Ts)]; 26.81 [3C,
C(CH3)3]; 31.71 [CH2CH2CH]]; 64.03 [CH2OTBDPS];
69.61 [CH2OTs]; 124.03 and 132.59 [2C, CH]CH]; 127.65
[4C, aromatics meta to Si]; 127.88, 129.64 and 129.79 [6C,
CH of Ts and aromatics para to Si]; 133.16 [C-Me (Ts)];
133.60 [2C, C ipso of Ph]; 135.49 [4C, aromatics ortho to
Si]; 144.68 [C–SO2]. (2) Transformation of 12 into 13.
A solution of crude tosylate from the previous reaction in
dry DMF (20 ml) was treated with potassium bromide
(1.41 g, 11.9 mmol) and heated at 100 8C for 35 min. The
crude was poured into water and extracted with Et2O. The
collected organic layers were washed with water and then
with brine. After solvent removal chromatography with PE/
Et2O 100:0/97.5:2.5 afforded pure 13 (2.48 g, 83% two
steps) as a colourless oil. Rf 0.35 (PE/Et2O 99:1, A, C).
Anal. found C, 62.65; H, 6.70. C21H27BrOSi requires C,
62.52; H, 6.75. IR: nmax 3303, 2930, 2855, 1422, 1110,
1051, 969, 919. GC–MS: Rt 9.96; m/z 348 (11), 347
[MC(81Br)K57, 46], 346 (11), 345 [MC(79Br)K57, 43],
265 (12), 264 (18), 263 (100), 262 (18), 261 (99), 211 (5.1),
204 (5.5), 203 (46), 202 (6.1), 201 (49), 200 (9.7), 199 (48),
197 (23), 187 (10), 183 (12), 182 (6.6), 181 (30), 180 (7.0),
155 (5.7), 152 (8.1), 145 (15), 143 (14), 135 (14), 123 (83),
121 (14), 117 (8.7), 115 (5.6), 105 (28), 91 (24), 79 (5.9), 78
(12), 77 (44), 68 (5.1), 67 (56), 65 (8.1), 57 (28), 53 (13), 51
1
67 (12), 43 (43). H NMR (200 MHz): 1.05 [9H, s, tBu];
1.26 [6H, t, CH2CH3, JZ7.2 Hz]; 1.83–1.94 [2H, m,
CH2CH2C]]; 2.04 [3H, s, CH3CO]; 2.42 [2H, centre of
m, CH2CH2C]]; 4.12 [2H, apparent d, CH2OTBDPS, JZ
3.0 Hz]; 4.24 [4H, q, CH2CH3, JZ7.1 Hz]; 5.47–5.69 [2H,
m, CH]CH]; 6.76 [1H, broad s, NH]; 7.32–7.43 [6H, m,
aromatics]; 7.64–7.69 [4H, m, aromatics]. 13C NMR
(50 MHz): 13.90 [2C, CH2CH3]; 19.13 [C(CH3)3]; 22.97
[CH3CO]; 26.46 [CH2CH2CH]]; 26.76 [3C, C(CH3)3];
31.53 [CH2CH2CH]]; 62.42 [2C, CH2CH3]; 64.20 [CH2-
OTBDPS]; 66.19 [C(CO2Et)2]; 127.56 [4C, aromatics meta
to Si]; 128.78 and 129.76 [2C, CH]CH]; 129.54 [2C,
aromatics para to Si]; 133.62 [2C, C ipso of Ph]; 135.44
[4C, aromatics ortho to Si]; 168.01 [2C, CO2Et]; 168.94
[CH3CO].
4.9. (G)-(E)-Ethyl 2-acetamido-7-[(t-butyldiphenyl-
silyl)oxy]hept-5-enoate 15
(1) Monohydrolysis. A solution of 14 (2.07 g, 3.88 mmol) in
96% EtOH (30 ml) was treated with 6 N aqueous NaOH
(832 ml) and stirred at rt for 4 h. In some cases, an additional
little amount of NaOH (0.2–0.3 mol equiv) was needed and
not always the reaction went to completion. It is, however,
preferred not to employ an excess of NaOH in order to avoid
the double saponification, while the unreacted malonate can
be easily recovered and recycled. A solution of concentrated
HCl (400 ml in 1.5 ml of 96% EtOH) was added, followed
by 5% aqueous NH4H2PO4. The mixture was concentrated
1
(11), 45 (31), 42 (5.0), 41 (75), 40 (5.4), 39 (23). H NMR
(200 MHz): 1.06 [9H, s, tBu]; 2.54–2.64 [2H, m,
CH2CH2C]]; 3.37 [2H, t, CH2CH2OH, JZ7.1 Hz]; 4.17–

L. Banfi et al. / Tetrahedron 62 (2006) 4331–4341
4337
under vacuo, partitioned between brine and AcOEt and
extracted with AcOEt, after adjusting the pH to 2. Rf 0.36
(PE/AcOEt 7:3C5% AcOH, A, B). (2) Decarboxylation.
The crude from the previous reaction was dissolved in
dioxane (20 ml) and refluxed under nitrogen for 1 h. After
solvent removal chromatography with PE/AcOEt 7:3/4:6
gave 15 as a pale yellow oil (1.50 g, 83%) (in some cases up
to 16% unreacted malonate can be recovered). Rf 0.31 (PE/
AcOEt 6:4, A, B). Anal. found C, 69.50; H, 7.85.
C27H37NO4Si requires C, 69.34; H, 7.97. IR: nmax 2990,
2955, 2928, 2855, 1730, 1669, 1602, 1110, 1037, 973.
GC–MS (usual method but with final temperature 290 8C):
Rt 12.30; m/z 411 (15), 410 (MCK57, 48), 200 (15), 199
(79), 197 (12), 183 (9.8), 181 (13), 180 (6.3), 166 (5.8), 139
(15), 138 (26), 137 (5.9), 135 (15), 123 (5.9), 121 (9.2), 105
(11), 102 (6.2), 97 (9.5), 96 (100), 91 (5.2), 81 (7.1), 79 (22),
78 (7.1), 77 (27), 74 (5.6), 68 (9.5), 67 (11), 60 (83), 57
(8.8), 45 (13), 44 (5.5), 43 (92), 42 (6.9), 41 (14). 1H NMR
(200 MHz): 1.05 [9H, s, tBu]; 1.29 [3H, t, CH2CH3, JZ
7.0 Hz]; 1.60–2.13 [4H, m, CH2CH2C]]; 2.02 [3H, s,
CH3CO]; 4.14 [2H, apparent d, CH2OTBDPS, JZ3.2 Hz];
4.21 [2H, q, CH2CH3, JZ7.2 Hz]; 4.61 [1H, dt, CHCO2Et,
JZ5.0, 7.6 Hz]; 5.47–5.72 [2H, m, CH]CH]; 5.98 [1H,
broad d, NH, JZ8.0 Hz]; 7.32–7.43 [6H, m, aromatics];
7.64–7.69 [4H, m, aromatics]. 13C NMR (50 MHz): 14.09
[CH2CH3]; 19.13 [C(CH3)3]; 23.08 [CH3CO]; 26.77 [3C,
C(CH3)3]; 27.91 [CH2CH2CH]]; 31.99 [CH2CH2CH]];
51.86 [CHCO2Et]; 61.35 [CH2CH3]; 64.24 [CH2OTBDPS];
127.55 [4C, aromatics meta to Si]; 128.92 and 129.96 [2C,
CH]CH]; 129.52 [2C, aromatics para to Si]; 133.67 [2C, C
ipso of Ph]; 135.44 [4C, aromatics ortho to Si]; 169.72 and
172.51 [2C, CO].
[2C, C ipso of Ph]; 135.53 [4C, aromatics ortho to Si];
169.73 and 171.83 [2C, CO].
4.11. General procedure for TBDPS removal
A solution of silyl ether (1.58 mmol) in dry THF (5 ml) was
cooled to 0 8C and treated with 0.7 M solution of nBu4NF in
THF (4.51 ml); after 10 min, the solution was allowed to stir
a rt for 2 h. After dilution with brine, an extraction with
AcOEt was performed.
4.11.1. (G)-(E)-Ethyl 2-acetamido-7-hydroxyhept-5-
enoate 17. Chromatography with AcOEt/MeOH 100:0/
8:2 gave 17 as a colourless oil in 96% yield. Rf 0.47 (AcOEt/
MeOH 95:5, B). Anal. found C, 57.60; H, 8.40. C11H19NO4
requires C, 57.62; H, 8.35. IR: nmax 3428, 3005, 2800, 1730,
1671, 1376, 1245, 1136, 1079, 973, 703. GC–MS: Rt 6.87;
m/z 229 (MC, 0.11), 186 (5.5), 156 (15), 152 (29), 138 (18),
124 (12), 123 (9.4), 114 (16), 112 (8.4), 103 (9.0), 102 (58),
97 (11), 96 (95), 95 (6.2), 94 (7.7), 86 (5.4), 84 (5.4), 82
(7.8), 81 (5.2), 80 (5.5), 79 (44), 78 (15), 74 (20), 70 (5.7),
69 (5.6), 68 (6.9), 67 (83), 60 (11), 57 (9.1), 56 (7.9), 55
(7.5), 44 (18), 43 (100), 42 (12), 41 (18), 39 (7.1). 1H NMR
(200 MHz): 1.22 [3H, t, CH2CH3, JZ7.1 Hz]; 1.59–2.11
[4H, m, CH2CH2C]]; 1.96 [3H, s, CH3CO]; 4.02 [2H,
broad s, CH2OH]; 4.14 [2H, q, CH2CH3, JZ7.2 Hz]; 4.56
[1H, dt, CHCO2Et, JZ5.4, 7.8 Hz]; 5.50–5.69 [2H, m,
CH]CH]; 6.01 [1H, broad d, NH, JZ8.0 Hz]. 13C NMR
(50 MHz): 13.98 [CH2CH3]; 22.83 [CH3CO]; 27.88 [CH2-
CH2CH]]; 31.52 [CH2CH2CH]]; 51.55 [CHCO2Et];
61.34 [CH2CH3]; 62.83 [CH2OH]; 130.18 and 130.56 [2C,
CHZCH]; 170.34 and 172.59 [2C, CO].
4.11.2. (G)-(E)-t-Butyl 2-acetamido-7-hydroxyhept-5-
enoate 18. Chromatography with AcOEt/MeOH 100:0/
9:1 gave 18 as a colourless oil in 80% yield. Rf 0.18 (AcOEt,
B). Anal. found C, 60.55; H, 9.10. C13H23NO4 requires C,
60.68; H, 9.01. IR: nmax 3429, 2978, 2871, 1723, 1667,
1370, 1193, 1153, 1075, 973. GC–MS: Rt 7.14; m/z 239
(MCK18, 0.099), 184 (8.4), 183 (14), 158 (8.2), 157 (12),
156 (18), 138 (15), 124 (26), 123 (8.0), 114 (21), 99 (7.1), 97
(10), 96 (100), 86 (5.9), 85 (7.1), 79 (21), 74 (9.4), 60 (9.2),
4.10. (G)-(E)-t-Butyl 2-acetamido-7-[(t-butyldiphenyl-
silyl)oxy]hept-5-enoate 16
(1) Hydrolysis of the ester. The same procedure described in
the above paragraph was followed starting from 363 mg
(777 mmol) of 15, using this time 1.7 mol equiv of 6 N
aqueous NaOH. Rf 0.46 (AcOEt/AcOH 95:5, A, B). (2)
Formation of the t-butyl ester. A solution of crude acid in
dry CH2Cl2 (20 ml) was treated with t-butyl-2,2,2-trichloro-
acetimidate (278 ml, 1.55 mmol) and stirred at rt for 1 h
10 min, before BF3$Et2O (8 ml, 65 mmol) was added. After
stirring for additional 2 h 20 min, solid NaHCO3 (17 mg)
was added and the crude was filtered and concentrated under
vacuo. Chromatography with PE/AcOEt 7:3/1:1 afforded
16 as a pale yellow oil (289 mg, 75% from 15). Rf 0.30
(PE/AcOEt 6:4, A, B). Anal. found C, 70.15; H, 8.30.
C29H41NO4Si requires C, 70.26; H, 8.34. IR: nmax 3019,
2926, 2857, 1726, 1667, 1603, 1369, 1192, 1153, 1111,
1056, 928, 876. GC–MS: not feasible. 1H NMR (200 MHz):
1.05 [9H, s, SitBu]; 1.47 [9H, s, OtBu]; 1.60–2.18 [4H, m,
CH2CH2C]]; 2.01 [3H, s, CH3CO]; 4.06–4.22 [2H, m,
CH2OTBDPS]; 4.51 [1H, dt, CHCO2tBu, JZ5.2, 7.6 Hz];
5.49–5.72 [2H, m, CH]CH]; 6.08 [1H, broad d, NH, JZ
7.6 Hz]; 7.32–7.43 [6H, m, aromatics]; 7.64–7.69 [4H, m,
aromatics]. 13C NMR (50 MHz): 19.21 [SiC(CH3)3]; 23.27
[CH3CO]; 26.83 [3C, SiC(CH3)3]; 27.92 [CH2CH2CH]];
28.00 [3C, OC(CH3)3]; 32.28 [CH2CH2CH]]; 52.42
[CHCO2Et]; 64.36 [CH2OTBDPS]; 82.22 [OC(CH3)3];
127.61 [4C, aromatics meta to Si]; 129.26 and 129.83
[2C, CH]CH]; 129.59 [2C, aromatics para to Si]; 133.74
1
57 (28), 44 (5.6), 43 (29), 41 (12). H NMR (200 MHz):
1.48 [9H, s, tBu]; 1.62–2.18 [4H, m, CH2CH2C]]; 2.02
[3H, s, CH3CO]; 4.09 [2H, broad s, CH2OH]; 4.53 [1H, dt,
CHCO2tBu, JZ5.0, 7.6 Hz]; 5.58–5.76 [2H, m, CH]CH];
6.05 [1H, broad d, NH, JZ7.8 Hz]. 13C NMR (50 MHz):
23.32 [CH3CO]; 27.93 [CH2CH2CH]]; 28.01 [3C,
C(CH3)3]; 32.19 [CH2CH2CH]]; 52.09 [CHCO2Et];
63.54 [CH2OH]; 82.31 [C(CH3)3]; 130.30 and 131.21 [2C,
CH]CH]; 169.69 and 171.80 [2C, CO].
4.11.3. (E)-Diethyl 2-acetamido-2-5-(hydroxypent-3-
enyl)malonate 19. Chromatography with PE/AcOEt
10:90/0:100 gave 19 as a colourless oil in 85% yield. Rf
0.44 (AcOEt, B). Anal. found C, 55.75; H, 7.80. C14H23NO6
requires C, 55.80; H, 7.69. IR: nmax 3411, 2978, 2868, 1736,
1673, 1474, 1370, 1265, 1089, 1010, 974, 856, 736.
GC–MS: Rt 7.85; m/z 301 (MC, 0.092), 228 (11), 217
(5.1), 186 (19), 179 (12), 178 (100), 175 (9.5), 174 (15), 171
(48), 169 (12), 168 (65), 164 (8.8), 151 (6.6), 143 (35), 140
(15), 129 (17), 125 (18), 123 (11), 122 (16), 116 (12), 115
(6.1), 112 (13), 101 (6.4), 95 (8.9), 94 (34), 93 (5.7), 88

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L. Banfi et al. / Tetrahedron 62 (2006) 4331–4341
(5.1), 84 (83), 80 (5.2), 79 (12), 71 (6.2), 70 (6.4), 68 (5.4),
67 (25), 55 (7.3), 54 (6.8), 53 (5.3), 43 (89), 42 (25), 41 (20),
39 (5.7). H NMR (300 MHz): 1.25 [6H, t, CH2CH3, JZ
2.22 [4H, m, CH2CH2C]]; 2.04 [3H, s, CH3CO]; 3.87–4.01
[2H, m, CH2Br]; 4.22 [2H, q, CH2CH3, JZ7.1 Hz]; 4.62 [1H,
dt, CHCO2Et, JZ5.0, 7.7 Hz]; 5.69–5.80 [2H, m, CH]CH];
6.06 [1H, broad d, NH, JZ7.6 Hz]. 13C NMR (50 MHz):
14.17 [CH2CH3]; 23.25 [CH3CO]; 27.85 [CH2CH2CH]];
31.74 [CH2CH2CH]]; 32.94 [CH2Br]; 51.62 [CHCO2Et];
61.62 [CH2CH3]; 127.54 and 134.39 [2C, CH]CH]; 169.77
and 172.36 [2C, CO].
1
7.1 Hz]; 1.87–1.94 [2H, m, CH2CH2C]]; 2.03 [3H, s,
CH3CO]; 2.44 [2H, centre of m, CH2CH2C]]; 4.56 [2H,
apparent d, CH2OH, JZ3.6 Hz]; 4.24 [4H, q, CH2CH3, JZ
7.2 Hz]; 5.55–5.69 [2H, m, CH]CH]; 6.79 [1H, broad s,
NH]. 13C NMR (75 MHz): 13.84 [2C, CH2CH3]; 22.85
[CH3CO]; 26.38 [CH2CH2CH]]; 31.35 [CH2CH2CH]];
62.46 [2C, CH2CH3]; 63.11 [CH2OH]; 66.12 [C(CO2Et)2];
130.09 and 130.49 [2C, CH]CH]; 167.94 [2C, CO2Et];
169.18 [CH3CO].
4.13.2. (G)-(E)-t-Butyl 2-acetamido-7-bromohept-5-
enoate 22. Chromatography with ETP/AcOEt 2:8 gave 22
as a white foam in 75% yield. Rf 0.50 (ETP/AcOEt 2:8,
A, B, C). Anal. found C, 48.75; H, 6.85. C13H22BrNO3
requires C, 48.76; H, 6.92. IR: nmax 3009, 2958, 1723, 1666,
1189, 1149, 1097, 1010, 922. GC–MS: Rt 7.60; m/z 248
[MC(81Br)K73, 3.1], 246 [MC(79Br)K73, 3.1], 220 (13),
218 (13), 185 (8.4), 184 (84), 178 (44), 176 (46), 142 (29),
140 (8.0), 138 (20), 97 (5.4), 96 (46), 86 (11), 85 (7.9), 81
(5.5), 79 (14), 74 (11), 60 (19), 57 (67), 56 (6.7), 53 (11), 44
(10), 43 (100), 42 (9.8), 41 (40), 39 (10). 1H NMR
(200 MHz): 1.48 [9H, s, tBu]; 1.63–2.18 [4H, m,
CH2CH2C]]; 2.02 [3H, s, CH3CO]; 3.86–4.02 [2H, m,
CH2Br]; 4.52 [1H, dt, CHCO2tBu, JZ5.4, 7.2 Hz]; 5.63–
5.84 [2H, m, CH]CH]; 6.04 [1H, broad d, NH, JZ7.6 Hz].
13C NMR (50 MHz): 23.32 [CH3CO]; 27.85 [CH2CH2-
CH]]; 28.02 [3C, C(CH3)3]; 31.95 [CH2CH2CH]]; 33.01
[CH2Br]; 52.22 [CHCO2Et]; 82.39 [C(CH3)3]; 127.36 and
134.68 [2C, CH]CH]; 169.65 and 171.54 [2C, CO].
4.12. (G)-(E)-Ethyl 2-acetamido-7-chlorohept-5-
enoate 20.
A solution of 17 (200 mg, 872 mmol) in dry CCl4 (1 ml) was
treated with PPh3 (366 mg, 1.40 mmol) and refluxed for 6 h.
The reaction was poured into NH4Cl saturated solution and
extracted with AcOEt. Chromatography with Et2O/AcOEt/
8:2 gave 20 as a pale yellow oil in 66% yield. Rf 0.42 (Et2O/
AcOEt 8:2, A, C). Anal. found C, 53.30; H, 7.45.
C11H18ClNO3 requires C, 53.33; H, 7.32. IR: nmax 3430,
2978, 1731, 1671, 1494, 1375, 1187, 1125, 1092, 966.
GC–MS: Rt 7.31; m/z 249 [MC(37Cl), 0.039], 247
[MC(35Cl), 0.12], 212 (40), 176 (5.9), 174 (18), 170 (12),
166 (9.5), 152 (14), 145 (6.5), 138 (18), 134 (25), 133 (5.4),
132 (77), 103 (5.1), 102 (23), 99 (15), 96 (46), 85 (5.5), 81
(5.0), 79 (22), 78 (5.1), 74 (12), 67 (7.3), 60 (17), 53 (14), 44
(8.5), 43 (100), 42 (11), 41 (12), 39 (8.0). 1H NMR
(200 MHz): 1.29 [3H, t, CH2CH3, JZ7.2 Hz]; 1.67–2.18
[4H, m, CH2CH2C]]; 2.03 [3H, s, CH3CO]; 4.02 [2H,
apparent d, CH2Cl, JZ6.2 Hz]; 4.21 [2H, q, CH2CH3, JZ
7.2 Hz]; 4.62 [1H, dt, CHCO2Et, JZ5.0, 7.8 Hz]; 5.57–5.83
[2H, m, CH]CH]; 6.08 [1H, broad d, NH, JZ7.4 Hz]. 13C
NMR (50 MHz): 14.16 [CH2CH3]; 23.24 [CH3CO]; 27.82
[CH2CH2CH]]; 31.77 [CH2CH2CH]]; 45.01 [CH2Cl];
51.74 [CHCO2Et]; 61.61 [CH2CH3]; 127.15 and 133.94
[2C, CH]CH]; 169.77 and 172.37 [2C, CO].
4.13.3. Diethyl 2-acetamido-2-5-(bromopent-3-enyl)-
malonate 23. Chromatography with PE/AcOEt/ 2:8/
0:100 gave 23 as a pale yellow oil in 92% yield. Rf 0.61
(Et2O, A, B, C). Anal. found C, 46.25; H, 6.05.
C14H22BrNO5 requires C, 46.17; H, 6.09. IR: nmax 3410,
3005, 1734, 1676, 1481, 1369, 1268, 1230, 1094, 1006, 969.
GC–MS: Rt 8.28; m/z 320 [MC(81Br)K45, 0.84], 318
[MC(79Br)K45, 0.84], 284 (30), 250 (17), 248 (19), 243
(6.1), 242 (42), 238 (5.2), 174 (7.3), 171 (5.0), 169 (11), 168
(98), 151 (5.1), 140 (9.9), 135 (5.3), 133 (6.9), 123 (9.4), 122
(8.6), 116 (5.6), 115 (14), 112 (5.2), 111 (8.3), 96 (6.1), 95
(9.4), 94 (34), 80 (5.0), 79 (15), 77 (6.0), 71 (83), 67 (28), 60
(6.9), 55 (5.3), 54 (8.1), 53 (16), 43 (100), 42 (19), 41 (22),
4.13. General procedure for the direct transformation
of alcohols into bromides
1
To a solution of alcohol (2.85 mmol) in dry CH3CN (15 ml),
previously cooled to 0 8C, PPh3 (4.27 mmol) and CBr4
(4.27 mmol) were added and, after 5 min, the resulting
solution was allowed to stir at rt for about 35 min. After
dilution with saturated aqueous NaHCO3, an extraction with
AcOEt was performed.
39 (7.5). H NMR (300 MHz): 1.22 [6H, t, CH2CH3, JZ
7.2 Hz]; 1.87–1.94 [2H, m, CH2CH2C]]; 2.01 [3H, s,
CH3CO]; 2.40 [2H, centre of m, CH2CH2C]]; 3.82–3.95
[2H, m, CH2Br]; 4.21 [4H, q, CH2CH3, JZ7.0 Hz]; 5.59–
5.73 [2H, m, CH]CH]; 6.77 [1H, broad s, NH]. 13C NMR
(75 MHz): 13.85 [2C, CH2CH3]; 22.91 [CH3CO]; 26.34
[CH2CH2CH]]; 31.08 [CH2CH2CH]]; 32.79 [CH2Br];
62.47 [2C, CH2CH3]; 66.02 [C(CO2Et)2]; 127.10 and
134.26 [2C, CH]CH]; 167.77 [2C, CO2Et]; 169.00
[CH3CO].
4.13.1. (G)-(E)-Ethyl 2-acetamido-7-bromohept-5-eno-
ate 21. Chromatography with Et2O/AcOEt 100:0/9:1 gave
21 as a white-gray solid in 88% yield. Crystallization from
CH2Cl2/iPr2O afforded white crystals. Mp: 70.1–70.6 8C
(CH2Cl2/iPr2O). Rf 0.51 (Et2O/AcOEt 8:2, A, B, C). Anal.
found C, 45.30; H, 6.15. C11H18BrNO3 requires C, 45.22; H,
6.21. IR: nmax 3428, 3004, 1730, 1670, 1376, 1193, 1019, 967.
GC–MS: Rt 7.31; m/z 248 [MC(81Br)K45, 1.1], 246
[MC(79Br)K45, 0.92], 220 (7.2), 219 (7.1), 213 (5.6), 212
(44), 178 (28), 176 (28), 170 (18), 166 (17), 138 (28), 102 (19),
97 (7.4), 93 (84), 85 (8.2), 81 (6.3), 79 (20), 74 (9.9), 67 (8.1),
60 (27), 53 (11), 44 (6.3), 43 (100), 42 (11), 41 (12), 39 (7.9).
1H NMR (200 MHz): 1.30 [3H, t, CH2CH3, JZ7.2 Hz]; 1.69–
4.14. General procedure for the SN20 cyclization
Several experiments have been performed, adding the
desired base to a solution of halide (compounds 20–23)
(for solvent and base, see Table 1) under argon. Reaction
times, temperatures, yields and dr are reported in Table 1.
Quenching with 5% aqueous NH4H2PO4 was followed by
extraction with AcOEt.

L. Banfi et al. / Tetrahedron 62 (2006) 4331–4341
4339
4.14.1. (2R*,5R*)- and (2R*,5S*)-Ethyl 1-acetyl-5-vinyl-
pyrrolidine-2-carboxylate 24a and 24b. Chromatography
with Et2O/AcOEt 8:2/6:4 gave diastereomeric products as
a pale yellow oil. The same chromatography also allowed to
obtain analytically pure diastereoisomers. trans Derivative
(2R*,5R*): Rf 0.40 (Et2O/AcOEt 8:2, B). Anal. found C,
62.60; H, 8.05. C11H17NO3 requires C, 62.54; H, 8.11. IR:
nmax 2956, 2919, 2853, 1735, 1631, 1407, 1177, 1094, 1011,
921. GC–MS: Rt 5.42; m/z 211 (MC, 2.3), 138 (30), 97 (7.2),
CHH]CH, JZ1.0, 10.2 Hz]; 5.43 [1H, dt, CHH]CH, JZ
1.0, 17.2 Hz]; 5.94 [1H, ddd; CH2]CH, JZ6.6, 10.6,
17.2 Hz]. 13C NMR (50 MHz): 22.20 [CH3CO]; 27.50 [C3];
28.01 [3C, C(CH3)3]; 32.42 [C4]; 60.83 and 61.72 [2C, C2
and C5]; 81.16 [C(CH3)3]; 116.36 [CH2]CH]; 138.25
[CH2]CH]; 169.82 and 169.89 [2C, CO].
4.14.3. (G)-Diethyl 1-acetyl-5-vinylpyrrolidine-2,2-
dicarboxylate 26. Chromatography with PE/Et2O 1:9/
0:100 gave diastereomeric products as a colourless oil. Rf
0.43 (Et2O, B). Anal. found C, 59.50; H, 7.40. C14H21NO5
requires C, 59.35; H, 7.47. IR: nmax 2978, 2869, 1735, 1654,
1394, 1191, 1128, 1092, 1016, 925. GC–MS: Rt 6.79; m/z
283 (MC, 3.6), 240 (2.5), 210 (6.6), 169 (10), 168 (100), 140
(5.3), 94 (4.7), 67 (3.5), 43 (5.0). 1H NMR (300 MHz): 1.28
and 1.27 [6H, 2t, CH2CH3, JZ7.2 Hz]; 1.73–2.47 [4H, m,
H3 and H4]; 2.06 [3H, s, CH3CO]; 4.23 [4H, centre of m,
CH2CH3]; 4.47 [1H, centre of m, H5]; 5.22 [1H, broad d,
CHH]CH, JZ10.5 Hz]; 5.40 [1H, dt, CHH]CH, JZ1.1,
17.1 Hz]; 5.86 [1H, ddd; CH2]CH, JZ5.7, 10.2, 16.8 Hz].
13C NMR (75 MHz): 13.90 and 13.96 [2C, CH2CH3]; 22.36
[CH3CO]; 31.27 and 33.64 [2C, C3 and C4]; 61.65 [C5];
61.87 and 61.95 [2C, CH2CH3]; 73.01 [C(CO2Et)2]; 116.48
[CH2]CH]; 137.54 [CH2]CH]; 168.58, 168.75 and
170.16 [3C, CO].
1
96 (100), 79 (7.1), 68 (9.1), 43 (25), 41 (9.0), 39 (5.1). H
NMR (200 MHz): 1.25 [3H, t, CH2CH3, JZ7.2 Hz]; 1.70–
2.42 [4H, m, H3 and H4]; 2.04 [3H, s, CH3CO]; 4.12–4.23
[2H, m, CH2CH3]; 4.37–4.60 [2H, m, H2 and H5]; 5.07
[1H, dt, CHH]CH, JZ1.2, 17.2 Hz]; 5.17 [1H, dt,
CHH]CH, JZ1.1, 10.4 Hz]; 5.80 [1H, ddd; CH2]CH,
JZ5.2, 10.2, 16.8 Hz]. 13C NMR (50 MHz): 14.11
[CH2CH3]; 22.06 [CH3CO]; 26.45 [C3]; 30.71 [C4]; 59.15
and 60.71 [2C, C2 and C5]; 61.02 [CH2CH3]; 115.18
[CH2]CH]; 137.64 [CH2]CH]; 170.27 and 172.14 [2C,
CO]. cis Derivative (2R*,5S*): Rf 0.30 (Et2O/AcOEt 8:2,
B). Anal. found C, 62.55; H, 8.15. C11H17NO3 requires C,
62.54; H, 8.11. IR: nmax 3002, 1737, 1637, 1406, 1375,
1356, 1194, 1029, 919. GC–MS: Rt 5.55; m/z 211 (MC, 8.8),
139 (5.2), 138 (59), 97 (6.7), 96 (100), 79 (5.4), 68 (5.2), 43
(8.7). 1H NMR (200 MHz): 1.28 [3H, t, CH2CH3, JZ
7.1 Hz]; 1.81–2.27 [4H, m, H3 and H4]; 2.05 [3H, s,
CH3CO]; 4.12–4.52 [4H, m, CH2CH3, H2 and H5]; 5.22
[1H, dt, CHH]CH, JZ1.1, 10.4 Hz]; 5.46 [1H, dt,
CHH]CH, JZ1.3, 17.2 Hz]; 5.93 [1H, ddd; CH2]CH,
JZ6.6, 10.2, 17.2 Hz]. 13C NMR (50 MHz): 14.15
[CH2CH3]; 22.13 [CH3CO]; 27.47 [C3]; 32.42 [C4]; 59.98
and 61.07 [2C, C2 and C5]; 61.63 [CH2CH3]; 116.52
[CH2]CH]; 137.97 [CH2]CH]; 170.14 and 172.26
[2C, CO].
4.15. (2R*,5R*)- and (2R*,5S*)-Ethyl 1-acetyl-5-vinyl-
pyrrolidine-2-carboxylate 24a,b from 26
The same two step procedure described to obtain compound
15 was followed to give 24a,b in 80% overall yield, as a
12:88 trans:cis mixture.
4.16. (2R*,5R*)- and (2R*,5S*)-1-Acetyl-2-hydroxy-
methyl-5-vinylpyrrolidine 27a and 27b
4.14.2. (2R*,5R*)- and (2R*,5S*)-t-Butyl 1-acetyl-5-
vinylpyrrolidine-2-carboxylate 25a and 25b. Chromato-
graphy with PE/AcOEt 4:6 gave separated diastereomeric
products as pale yellow oils. The relative configuration was
established to be trans for the major and cis for the minor
product on the basis of spectroscopic analogies with the
ethyl ester series. trans Derivative (2R*,5R*): Rf 0.37 (PE/
AcOEt 4:6, B). Anal. found C, 65.40; H, 8.80. C13H21NO3
requires C, 65.25; H, 8.84. IR: nmax 3001, 1731, 1632, 1407,
1368, 1150. GC–MS: Rt 5.79; m/z 239 (MC, 2.4), 166 (7.0),
139 (8.0), 138 (67), 97 (11), 96 (100), 94 (6.1), 79 (9.3), 68
(9.2), 67 (5.8), 57 (15), 43 (29), 41 (17), 39 (7.0). 1H NMR
(200 MHz): 1.45 [9H, s, C(CH3)3]; 1.62–2.42 [4H, m, H3
and H4]; 2.04 [3H, s, CH3CO]; 4.26–4.52 [2H, m, H2 and
H5]; 5.07 [1H, dt, CHH]CH, JZ1.2, 16.8 Hz]; 5.16 [1H,
broad d, CHH]CH, JZ10.6 Hz]; 5.80 [1H, ddd;
CH2]CH, JZ5.4, 10.6, 17.2 Hz]. 13C NMR (50 MHz):
22.13 [CH3CO]; 26.52 [C3]; 27.98 [3C, C(CH3)3]; 30.72
[C4]; 59.95 and 60.78 [2C, C2 and C5]; 81.17 [C(CH3)3];
115.08 [CH2]CH]; 137.91 [CH2]CH]; 170.10 and 171.40
[2C, CO]. cis Derivative (2R*,5S*): Rf 0.23 (PE/AcOEt 4:6,
B). Anal. found C, 65.30; H, 8.90. C13H21NO3 requires C,
65.25; H, 8.84. IR: nmax 3005, 1732, 1633, 1407, 1240,
1097, 1009, 924. GC–MS: Rt 5.88; m/z 239 (MC, 1.3), 139
(5.4), 138 (46), 97 (7.3), 96 (100), 79 (5.6), 68 (5.4), 57
Dry CaCl2 (274 mg, 2.47 mmol) was suspended in a
solution of dry THF–EtOH (2/1, 4.5 ml) and cooled to
K20 8C. Solid NaBH4 (156 mg, 4.12 mmol) was rapidly
added and the resulting slurry was stirred for 30 min at
K20 8C. A solution of ester 24 (174 mg, 823 mmol) in dry
THF (4 ml) was added and the reaction was allowed to stir at
the same temperature overnight. Quenching with a 2:1
solution of NH4Cl (satd soln)/KH2PO4 (1 M) was followed
by addition of AcOEt and filtration over a Celite pad. After
saturation with solid NaCl, the extraction was performed
with AcOEt/MeOH 9:1. The crude can then be used as such
for the following reaction, or purified by chromatography
with AcOEt/MeOH 100:0/95:5 to give pure alcohol as a
colourless oil (124 mg, 89%). trans Derivative (2R*,5R*):
Rf 0.36 (AcOEt/MeOH 95:5, B). Anal. found C, 63.70; H,
8.90. C9H15NO2 requires C, 63.88; H, 8.93. IR: nmax 3389,
2985, 2876, 1608, 1411, 1064, 993, 968, 924. GC–MS
(parameters changed in the usual method: init. temperature
80 8C, init. time 2 min, rate 10 8C/min, final temperature
260 8C, final time 4 8C, inj. temperature 200 8C): Rt 8.26;
m/z 169 (MC, 2.4), 151 (1.4), 139 (5.2), 138 (41), 97 (7.1),
1
96 (100), 79 (12), 68 (6.3), 43 (23), 41 (7.2), 39 (5.5). H
NMR (300 MHz): 1.60–2.24 [4H, m, H3 and H4]; 2.06 [3H,
s, CH3CO]; 3.61–3.75 [2H, m (became the AB part of an
ABX system after exchange with D2O, n: 3.59 and 3.70,
JABZ11.1 Hz, JAX, JBXZ3.6, 7.8 Hz), CH2OH]; 4.30–4.41
[2H, m, H2 and H5]; 4.72 [1H, broad s, OH]; 5.05 [1H, d,
1
(8.7), 43 (16), 41 (9.4). H NMR (200 MHz): 1.47 [9H, s,
C(CH3)3]; 1.67–2.35 [4H, m, H3 and H4]; 2.04 [3H, s,
CH3CO]; 4.22–4.70 [2H, m, H2 and H5]; 5.21 [1H, dt,

4340
L. Banfi et al. / Tetrahedron 62 (2006) 4331–4341
CHH]CH, JZ17.1 Hz]; 5.19 [1H, d, CHH]CH, JZ
10.5 Hz]; 5.78 [1H, ddd; CH2]CH, JZ5.4, 10.2, 17.1 Hz].
13C NMR (75 MHz): 22.96 [CH3CO]; 25.40 [C3]; 30.56
[C4]; 60.65 and 61.74 [2C, C2 and C5]; 66.11 [CH2OH];
115.04 [CH2]CH]; 137.42 [CH2]CH]; 172.46 [CO]. cis
Derivative (2R*,5S*): Rf 0.43 (AcOEt/MeOH 95:5, B).
Anal. found C, 63.75; H, 8.85. C9H15NO2 requires C, 63.88;
H, 8.93. IR: nmax 3403, 3344, 2956, 2872, 1612, 1410, 1358,
1252, 1198, 1085, 1009, 926. GC–MS (parameters changed
in the usual method: init. temperature 80 8C, init. time
2 min, rate 10 8C/min, final temperature 260 8C, final time
4 8C, inj. temperature 200 8C): Rt 8.30; m/z 169 (MC, 1.7),
151 (1.4), 139 (5.3), 138 (44), 97 (6.8), 96 (100), 79 (12), 68
(5.3), 43 (24), 41 (7.2), 39 (5.4). 1H NMR (200 MHz): 1.47–
2.18 [4H, m, H3 and H4]; 2.10 [3H, s, CH3CO]; 3.56–3.65
[2H, m (became the AB part of an ABX system after
(MC, 0.36), 151 (13), 138 (27), 109 (5.2), 97 (7.0), 96 (100),
94 (2.7), 81 (2.5), 79 (6.9), 68 (2.8), 67 (3.1), 54 (2.5), 43
(27), 41 (4.1), 39 (2.7). H NMR (300 MHz): 1.60–2.20
1
[4H, m, H3 and H4]; 2.04 and 2.06 [6H, 2s, CH3CO]; 4.19
and 4.28 [2H, AB part of an ABX system, CH2OAc, JAB
Z
10.9 Hz, JAX, JBXZ3.8, 6.8 Hz]; 4.10–4.41 [2H, m, H2 and
H5]; 5.18 [1H, d, CHH]CH, JZ9.9 Hz]; 5.19 [1H, d,
CHH]CH, JZ17.1 Hz]; 5.79 [1H, ddd; CH2]CH, JZ6.6,
10.2, 17.1 Hz]. 13C NMR (75 MHz): 20.87 and 22.68 [2C,
CH3CO]; 26.33 [C3]; 31.63 [C4]; 56.61 and 61.71 [2C, C2
and C5]; 64.37 [CH2OAc]; 115.54 [CH2]CH]; 138.85
[CH2ZCH]; 170.73 and 170.80 [2C, CO].
4.18. (2R*,5R*)- and (2R*,5S*)-2,5-Bis(acetoxymethyl)-
1-acetylpyrrolidine 29a and 29b
exchange with D2O, n: 3.61 and 3.69, JABZ11.5 Hz, JAX
,
(1) Ozonolysis. A solution of 28 (100 mg, 475 mmol) in dry
CH2Cl2/MeOH (1:1, 10 ml) was cooled to K78 8C and
ozonolyzed for about 5 min (at maximum power and at a
flow of 90 l/h). Ozone production was interrupted and the
apparatus was put under a static nitrogen atmosphere. Then
the solution was treated with 105 ml of Me2S, followed by
addition of NaBH4 (54 mg, 1.42 mmol). The temperature
was allowed to rise to 0 8C in 2 h and the reaction was stirred
for additional 5 min at rt. Slowly, addition of NH4Cl satd
soln was followed by dilution with few ml of brine and
extraction with CHCl3/MeOH 9:1. After solvent removal
the crude yellow oil was submitted directly to acetylation.
(2) Acetylation. The same procedure described for the
preparation of 28 from 27 was followed. However, since the
starting alcohols cannot be detected in TLC, an equivalent
amount of the reagents was added again after 1 h and the
resulting solution was stirred at rt for 2 h. Chromatography
with AcOEt/MeOH 100:0/95:5 gave 29 as a colourless oil
in 80% overall yield. Since compounds 29 were difficult to
be detected in TLC (iodine) the chromatographic purifi-
cation was followed by GC–MS. trans Derivative
(2R*,5R*): Rf 0.44 (AcOEt, B). HPLC (hexane/iPrOH
87:13, 0.8 ml/min, l 220 nm): Rt 15.92 and 17.41 min. Anal.
found C, 55.95; H, 7.35. C12H19NO5 requires C, 56.02; H,
7.44. IR: nmax 2999, 1738, 1631, 1385, 1187, 1031. GC–MS
(parameters changed in the usual method: init. temperature
80 8C, init. time 2 min, rate 7 8C/min, final temperature
200 8C, then: rate 20 8C/min, final temperature 260 8C, final
time 4 8C): Rt 15.80; m/z 257 (MC, 0.0099), 197 (7.1), 184
(14), 155 (5.4), 143 (11), 142 (100), 100 (46), 82 (38), 69
(7.1), 68 (12), 55 (18), 43 (76), 42 (7.9), 41 (7.8). 1H NMR
(300 MHz): 1.80–2.18 [4H, m, H3 and H4]; 2.03, 2.06 and
2.16 [9H, 3s, CH3CO]; 3.83 and 4.14 [2H, 2 dd, CH2OAc,
JZ8.1, 10.5; 7.8, 10.8 Hz]; 4.04 and 4.29 [2H, 2 broad dt,
H2 and H5, JZ3.9, 7.7; 3.3, 7.1 Hz]; 4.15 and 4.20 [2H, AB
JBXZ2.0, 8.0 Hz), CH2OH]; 4.40 and 4.18 [2H, centrers of
2 m, H2 and H5]; 5.19 [1H, dt, CHH]CH, JZ1.3, 18.2 Hz];
5.22 [1H, dt, CHH]CH, JZ1.3, 9.4 Hz]; 5.52 [1H, broad d,
OH, JZ7.4 Hz]; 5.80 [1H, ddd; CH2]CH, JZ5.6, 10.6,
16.8 Hz]. 13C NMR (50 MHz): 22.63 [CH3CO]; 26.44
[C3]; 30.71 [C4]; 62.60 and 62.63 [2C, C2 and C5];
67.48 [CH2OH]; 115.89 [CH2]CH]; 137.82 [CH2]CH];
172.94 [CO].
4.17. (2R*,5R*)- and (2R*,5S*)-2-Acetoxymethyl-1-
acetyl-5-vinylpyrrolidine 28a and 28b
A solution of 27 (110 mg, 650 mmol) in dry CH2Cl2 (3 ml)
was cooled to 0 8C and treated with Et3N (270 ml,
1.94 mmol), Ac2O (184 ml, 1.94 mmol) and 4-(dimethyl-
amino)pyridine (7.9 mg, 64.8 mmol). After 5 min the
reaction mixture was stirred at rt for 1–2 h and then diluted
with water and extracted with CH2Cl2. Chromatography
with AcOEt/MeOH 100:0/98:2 gave 28 as a colourless oil
(123 mg, 90%). When the reaction was performed on crude
alcohol the overall yield from 24 was 82%. trans Derivative
(2R*,5R*): Rf 0.60 (AcOEt/MeOH 95:5, B). Anal. found C,
62.65; H, 8.00. C11H17NO3 requires C, 62.54; H, 8.11. IR:
nmax 2957, 1729, 1640, 1401, 1247, 1186, 1029, 991, 919.
GC–MS (parameters changed in the usual method: init.
temperature 80 8C, init. time 2 min, rate 7 8C/min, final
temperature 200 8C, then: rate 20 8C/min, final temperature
260 8C, final time 4 8C): Rt 11.82; m/z 211 (MC, 1.5), 151
(12), 138 (33), 126 (2.7), 109 (3.5), 97 (6.7), 96 (100), 79
(5.1), 68 (3.5), 43 (24), 41 (4.2). 1H NMR (300 MHz): 1.68–
2.32 [4H, m, H3 and H4]; 2.01 and 2.03 [6H, 2s, CH3CO];
4.12 and 4.25 [2H, AB part of an ABX system, CH2OAc,
JABZ10.7 Hz, JAX, JBXZ3.1, 7.3 Hz]; 4.00–4.39 [2H, m,
H2 and H5]; 5.03 [1H, dt, CHH]CH, JZ1.0, 17.1 Hz]; 5.16
[1H, dt, CHH]CH, JZ1.0, 10.5 Hz]; 5.79 [1H, ddd;
CH2]CH, JZ5.4, 10.5, 17.1 Hz]. 13C NMR (75 MHz):
20.76 and 22.91 [2C, CH3CO]; 24.59 [C3]; 30.33 [C4];
55.91 and 60.82 [2C, C2 and C5]; 63.05 [CH2OAc]; 114.82
[CH2]CH]; 137.86 [CH2]CH]; 170.46 and 170.64 [2C,
CO]. cis Derivative (2R*,5S*): Rf 0.41 (AcOEt/MeOH 95:5,
B). Anal. found C, 62.70; H, 8.20. C11H17NO3 requires C,
62.54; H, 8.11. IR: nmax 2925, 2852, 1732, 1630, 1402,
1185, 1081, 989. GC–MS (parameters changed in the usual
method: init. temperature 80 8C, init. time 2 min, rate 7 8C/
min, final temperature 200 8C, then: rate 20 8C/min, final
temperature 260 8C, final time 4 8C): Rt 11.94; m/z 211
part of an ABX system, CH2OAc, JABZ10.8 Hz, JAX
,
JBXZ2.0, 3.1 Hz]. 13C NMR (75 MHz): 20.76, 20.88 and
22.75 [3C, CH3CO]; 25.31 and 27.27 [2C, C3 and C4]; 56.05
and 57.08 [2C, C2 and C5]; 63.10 and 64.40 [2C, CH2OAc];
169.82, 170.54 and 170.70 [3C, CO]. cis Derivative
(2R*,5S*): Rf 0.31 (AcOEt, B). HPLC (hexane/iPrOH
87:13, 0.8 ml/min, l 220 nm): 12.65 min. Anal. found C,
56.15; H, 7.40. C12H19NO5 requires C, 56.02; H, 7.44. IR:
nmax 2997, 1736, 1632, 1385, 1365, 1199, 1036. GC–MS
(parameters changed in the usual method: init. temperature
80 8C, init. time 2 min, rate 7 8C/min, final temperature
200 8C, then: rate 20 8C/min, final temperature 260 8C, final

L. Banfi et al. / Tetrahedron 62 (2006) 4331–4341
4341
time 4 8C): Rt 15.65; m/z 214 (MCK43, 0.11), 197 (5.2),
184 (7.3), 143 (8.7), 142 (100), 100 (41), 82 (37), 69 (5.2),
Maeda, K.; Tadano, K.; Ogawa, S. Tetrahedron 1994, 50,
5681–5704. Hirai, Y.; Shibuya, K.; Fukuda, Y.; Yokoyama,
H.; Yamaguchi, S. Chem. Lett. 1997, 221–222. Hirai, Y.;
Watanabe, J.; Nozaki, T.; Yokoyama, H.; Yamaguchi, S.
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Yamaguchi, S.; Hirai, Y. Tetrahedron Lett. 1998, 39,
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1
68 (9.7), 55 (18), 43 (80), 42 (8.0), 41 (7.5). H NMR
(300 MHz): 1.69–2.16 [4H, m, H3 and H4]; 2.06, 2.09 and
2.16 [9H, 3s, CH3CO]; 3.94–4.33 [5H, m, CH2OAc, H2 or
H5]; 4.33 [1H, dd, H2 or H5, JZ4.8, 12.6 Hz]. 13C NMR
(75 MHz): 20.82, 20.93 and 22.58 [3C, CH3CO]; 25.54 and
27.46 [2C, C3 and C4]; 56.46 and 57.47 [2C, C2 and C5];
64.06 and 64.94 [2C, CH2OAc]; 170.43, 170.68 and 170.73
[3C, CO].
Acknowledgements
The authors gratefully thank Stefano Nuvoloni and Eliana
Rondanina for their precious collaboration, Andrea Galatini
and Valeria Rocca for performing HPLC analyses and
MIUR (PRIN 00 and 02) and Compagnia di S. Paolo, Torino
for financial support.
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13. Preliminary data on this work were presented at the 2nd
International Conference on Multi Component Reactions,
Combinatorial and Related Chemistry (MCR2003), Genova
(I), April 14–16, 2003.
14. Guanti, G.; Perrozzi, S.; Riva, R. Tetrahedron: Asymmetry
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