Stereoselective synthesis of azetidine-derived glutamate and aspartate analogues from chiral azetidin-3-ones

Article abstract of DOI:10.1016/j.tet.2008.08.001

The stereoselective syntheses of cis conformationally constrained glutamate and aspartate analogues, containing an azetidine framework were accomplished from (S)-N-tosyl-2-phenylglycine in moderate overall yields. The key steps in these syntheses involved

Full text of DOI:10.1016/j.tet.2008.08.001

Tetrahedron 64 (2008) 9928–9936
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of azetidine-derived glutamate and aspartate analogues
from chiral azetidin-3-ones
,
Antonio Carlos B. Burtoloso a, Carlos Roque D. Correia b
*
a Instituto de Qu´ımica de S˜ao Carlos, Universidade de S˜ao Paulo, CP 780, CEP 13566-970, S˜ao Carlos, S˜ao Paulo, Brazil
b Instituto de Qu´ımica, Universidade Estadual de Campinas, UNICAMP, CP 6154, CEP 13083-970, Campinas, S˜ao Paulo, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 March 2008
Received in revised form 19 July 2008
Accepted 1 August 2008
Available online 8 August 2008
The stereoselective syntheses of cis conformationally constrained glutamate and aspartate analogues,
containing an azetidine framework were accomplished from (S)-N-tosyl-2-phenylglycine in moderate
overall yields. The key steps in these syntheses involved an efficient Wittig olefination of an azetidin-3-
one, followed by a highly stereoselective rhodium catalyzed hydrogenation. The route could also be
applied to the synthesis of a trans glutamate analogue, since epimerization of cis to trans isomer could be
performed using DBU in toluene at reflux.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
considerable attention lately, especially for their increased rigidity
and the interesting physiological activities exhibited by some aze-
Glutamate and aspartate are the predominant excitatory amino
acid (EAA) neurotransmitters in the mammalian central nervous
system.1 These excitatory amino acids activate a family of ligand-
gated ion channels, called ionotropic receptors (AMPA, KA, and
NMDA), and a family of receptors coupled to GTP-binding proteins
(metabotropic receptors) implicated in a variety of intracellular
signaling processes.2 EAA receptors participate in fast excitatory
transmission as well as in more complex signaling processes, such
as those required for synaptic plasticity and higher cognitive
functions.3 In contrast to these normal signaling pathways, exces-
sive activation of the ionotropic EAA receptors can trigger a cascade
of events that eventually leads to neuronal death. This process,
referred to as excitotoxicity, is thought to be the underlying path-
ological mechanism in a wide variety of neurological insults and
degenerative disorders, such as ischemia, trauma, hypoglycemia,
epilepsy, Huntington’s, and Parkinson’s diseases.4 To better un-
derstand the role of glutamate and aspartate in these diseases,
many research groups have investigated the interactions between
synthetic amino acids and the proteins to which glutamate and
aspartate bind. Conformationally restricted glutamate and aspar-
tate analogues are molecular probes, which have proved highly
valuable in providing information about the structural
requirements for binding to the EAA receptors.
tidine amino acids. Figure 1 shows some illustrative examples of
azetidine containing amino acids displaying important biological
activities.6a–d
Glutamate 1 has been shown to act as an activator of the
metabotropic receptors, whereas analogue 2 appears to be a potent
agonist of the kainate receptor. Compounds 2 and 3 also inhibit
sodium-dependent glutamate uptake.
2. Results and discussion
In spite of several interesting examples in the literature dealing
with the synthesis of azetidine amino acids,6 the synthesis of glu-
tamate and aspartate analogues has been accomplished in most
cases with some limitations such as low stereoselectivity, racemic
synthesis, or restriction to the synthesis of the trans analogues.
O
O
OH
O
H
OH
N
OH
O
H
N
OH
2
1
Although the majority of the glutamate and aspartate analogues
synthesized so far display a pyrrolidine ring,5 the use of azetidine
rings as conformational constraining elements has been attracting
O
O
O
O
OH
OH
HO
HO
N
N
3b
H
H
3a
* Corresponding author. Tel.: þ55 19 3521 3086; fax: þ55 19 3521 3023.
E-mail address: roque@iqm.unicamp.br (C.R.D. Correia).
Figure 1. Some azetidine-derived glutamate and aspartate analogues displaying
pharmacological activities.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.001

A.C.B. Burtoloso, C.R.D. Correia / Tetrahedron 64 (2008) 9928–9936
9929
Recently, we have published a communication reporting the syn-
thesis of the (2R,3S)-2-carboxyazetidine-3-acetic acid, a new cis
glutamate analogue.7a Herein, as an extension of our studies in-
volving the chemistry of azetidin-3-ones,7 we wish to report in
detail a straightforward route, which permits the preparation of
both cis and trans azetidine-containing aspartate and glutamate
analogues from a common intermediate, as depicted in Scheme 1.
Some alternative routes investigated by us failed to furnish these
rigidified amino acids, but provided pertinent information about
the behavior of four-membered rings.
enoate 6 was initially carried out using Pd/C in MeOH under H2
atmosphere. Under these conditions, only 19% of the desired ester 7
was obtained, together with 81% of the hydrogenolysis derived
product 8 (Scheme 2).
Compound 8 was the result of a hydrogenolysis reaction of the
N–C2 bond of 6 and was totally suppressed when hydrogenation
was performed using Rh/C as catalyst or Et3SiH in the presence of
Wilkinson’s catalyst.12 Under these conditions the cis ester 713 was
obtained in good yields (90% and 80%, respectively) with good
diastereoselectivities (92:08 and 88:12, cis/trans ratio, respectively)
(Scheme 3).
After finding the best conditions to perform the reduction of
enoate 6, we then proceeded in the synthesis of the glutamate
analogue by oxidizing the phenyl ring of 7 to a carboxylic acid
OH
OH
O
O
O
O
14
function. The ester 7 was then treated with RuCl3 and NaIO4
N
H
N
H
followed by the addition of diazomethane to furnish the cis diester
915 in yields ranging from 40 to 54% (Scheme 3). Next, hydrolysis of
the diester 9 with LiOH16 gave the N-protected glutamate acid
derivative 10 as a white solid (90% yield) with no detectable epi-
merization at C2. Although the major cis compounds 7, 9, and 10
could not be separated from their respective trans isomers (at C3)
by column chromatography, a careful recrystallization (ethanol/
hexane) of diacid 10 provided this key compound in an almost pure
form (dr>98:02 after a single recrystallization). Completion of the
synthesis of the novel conformational restricted cis azetidine glu-
tamate 11 was carried out as previously reported7a (N-deprotection
of diacid 10 with Na/naphthalene17 in quantitative yield, after
purification on ion-exchange resin).
OH
OH
glutamate analogues
OEt
O
Wittig
reaction
O
N
Rh catalysed
hydrogenation
Ts
N
Ts
azetidin-3-one
O
O
HO
HO
After completion of the synthesis of the cis glutamate analogue
11 and just to check the expandability of the present strategy, we
examined the epimerization of the cis diester 12 (prepared from
diacid 10 with trimethylsilyl-diazomethane) to its trans stereoiso-
mer. The use of bases such as LHMDS, KHMDS, t-BuOK, proton
sponge, Me2NH, and pyridine led to no epimerization18 at C2 or to
decomposition of the diester 12. However, reaction of diester 12
with DBU (10 equiv) in toluene at reflux for 7 h provided a di-
astereomeric mixture of diester 12 and its trans isomer (inseparable
mixture) in a 20:80 (GC)19 ratio as described in Table 1, entry 12.
After the synthesis of glutamate analogue 11, we focused on the
synthesis of the aspartate analogues. The same strategy employing
a Wittig olefination reaction, followed by hydroboration and oxida-
tion, was investigated starting from azetidin-3-one 167c (Scheme 4).
We began this study by preparing azetidin-3-one 16 in a similar
way to that described for azetidin-3-one 5, employing an N–H in-
sertion reaction of diazoketones. Under these conditions,
compound 16 could be prepared in 52% yield after three steps from
O
O
N
H
N
H
OH
OH
aspartate analogues
Scheme 1. Strategy for the synthesis of azetidine-derived glutamate and aspartate
analogues from azetidin-3-ones.
We began our study with the synthesis of the glutamate ana-
logues. The synthesis of glutamate analogues featured a very effi-
cient Wittig olefination of an azetidin-3-one8 (azetidine-3-ones can
be readily prepared from commercially available amino acids),
followed by a highly stereoselective rhodium catalyzed hydroge-
nation. For this purpose, azetidin-3-one 59 was readily prepared in
two steps from (S)-N-tosyl-2-phenylglycine in good overall yield
(Scheme 2). The protocol involved the conversion of N-protected
phenylglycine to the diazoketone 4 in 64%, followed by the reaction
of 4 with copper(II) acetate in benzene at reflux to promote the N–H
insertion reaction in 70% yield.7,10 Next, azetidin-3-one 5 was
converted to the enoate 6 in quantitative yield by a Wittig
olefination reaction11 using the stabilized ylide carboethoxy-
ethylidene-triphenylphosphorane. Catalytic hydrogenation of
N-Ts-L-serine 13 (Scheme 5). Next, azetidin-3-one 16 was submitted
to a Wittig olefination11 in the presence of the non-stabilized ylide
PPh3]CH2. However, formation of olefin 17 could not be detected
.
O
1. ClCOCOCl,
Cu(OAc)2 H2O, 10 mol%
C6H6 reflux, 1 min
O
O
CH2Cl2, DMF, 2h
H
OH
N
2. THF, CH2N2
70%
Ts
HNTs
5
N2
4
HNTs
64%
(S)-N-tosyl-2-phenylglycine
PPh3CHCOOEt
C6H6, reflux,
1 h
H2, MeOH, Pd/C
10 mol%, 24h
EtO
EtO
EtO
+
O
O
6
N
N
O
NH
Ts
7
8
Ts
Ts
quantitative (E+Z mixture)
19%
inseparable mixture
81%
Scheme 2. Synthesis of ester 7 from azetidin-3-one.

9930
A.C.B. Burtoloso, C.R.D. Correia / Tetrahedron 64 (2008) 9928–9936
1. NaIO4, RuCl3,
H2, MeOH,
O
AcOEt, H2O,
CH3CN, 3h
C6H6,
Rh/C 5 mol%,
24h
H
H
N
EtO
EtO
EtO
OMe
HO
2. CH2N2, Et2O
O
O
O
7
N
N
9
6
Ts
Ts
Ts
dr = 92:08 (GC)
40-54%
90%
ester 7 cis:trans
LiOH
THF:H2O
Condition
H2, Pd/C
O
19%
95:05
O
Na/C10H8
THF
HO
H2, Pt/C
Et3SiH
0%
OH
OH
O
80%
88:12
92:08
O
N
N
10
11
Ts
H
H2, Rh/C
90%
90%
quantitative
dr >98:02 (GC)
after recrystallization (EtOH/hexane)
dr = > 95:05 (1H NMR)
glutamate analogue
Scheme 3. Synthesis of the glutamate analogue 11 from ester 7.
30–50% of the tert-butyldiphenylsilyl alcohol supports this hy-
pothesis, this proposal is still speculative (Scheme 5). Nevertheless,
this problem was circumvented by the use of the Petasis reagent20
as the olefination source. In this case, olefin 17 could be prepared in
a moderate yield of 40%.
We next investigated the hydroboration reaction of olefin 17
in the presence of BH3$SMe2 complex. Surprisingly, we obtained
the expected primary alcohol 18 together with its regioisomer
(tertiary alcohol 19) in 50% yield as a 3:1 separable mixture
(Scheme 6).
Table 1
Epimerization studies with cis diester 12
O
O
epimerization
conditions
MeO
MeO
OMe
OMe
O
N
O
N
Ts
Ts
cis isomer 12
cis:trans = 98:2
trans isomer
Entry Epimerization conditions Result
cis Ester trans Ester
(%) (GC)
(%) (GC)
The unexpected formation of alcohol 19, considering the
hydroboration preferences, could be understood after carrying out
1
2
3
4
Me2NH, C6H6/H2O, FTC
Pyridine, CH2Cl2
Et3N, CH2Cl2
KHMDS, THF, ꢀ78
No epimerization
No epimerization
No epimerization
98
98
98
02
02
02
some semi-empirical (PM3) and ab initio (B3LYP/6-31G ) calcula-
*
tions. In these calculations, we found out that the HOMO co-
efficients of the two olefinic carbons (C3 and C5) of compound 17
are almost identical. Also unexpected, the non-terminal C3 has
a higher electron density than the terminal C5. Although steric
effects are predominating during the hydroboration reaction, fur-
nishing primary alcohol 18 as the major isomer, these two results
with the theoretical calculations support the isolation of the ter-
tiary alcohol in an unexpected proportion. The use of bulky borane
reagents was also employed, but was fruitless regarding yields and
selectivities. Aiming at the synthesis of the azetidine-derived as-
partate analogue, primary alcohol 18 was then converted to diol 20
and submitted to Jones oxidation conditions. Unfortunately this
protocol led to the formation of lactone 22 in 60% yield instead of
the desired diacid 21 (however, the formation of 22 is a chemical
proof of the cis relationship of compound 20). This transformation
involves a selective oxidation of the hydroxymethyl group at C3 to
an intermediate aldehyde, cyclization to a lactol followed by
oxidation.
Decomposition of 12
and 0 ꢁC, 300
5
LiHMDS, THF, ꢀ78
and 0 ꢁC, 300
Decomposition of 12
6
7
8
9
10
11
12
13
t-BuOꢀKþ, t-BuOH, 1 h
Proton sponge, CH2Cl2
DBU, CH2Cl2
Decomposition of 12
No epimerization
Epimerization
No epimerization
Epimerization
Epimerization
Epimerization
Epimerization
98
51
98
55
20
20
20
02
49
02
45
80
80
80
DBU, C6H6
DBU, C6H6, 60–70 ꢁ
C
DBU, C6H6, reflux, 24 h
DBU, PhMe, reflux, 7 h
DBU, xylene, reflux
and decomposition
No epimerization
(hydrolysis)
14
KOH, H2O:THF
98
02
even after varying the experimental conditions such as the use of
different solvents, temperatures, and bases. It is likely that the non-
stabilized ylide act as a base removing the hydrogen at C4 thus
preventing the desired Wittig olefination. Although the isolation of
In view of the results described above and with the objective of
circumventing the formation of lactone 22, we applied the same
sequence of reactions described in Schemes 5 and 6 on azetidin-3-
one 5. Once again, Petasis olefination followed by hydroboration
furnished only moderate yields of the desired products. Curiously,
hydroboration in this case provided the desired primary alcohol in
an even lower ratio when compared to the one described in Scheme
6. These results led us to look for alternative routes to the synthesis
of the aspartate analogues.
One of these alternatives was the cyanation of 3-mesyloxy
azetidines to construct the carboxylic acid function instead of the
Wittig reaction, as depicted in Scheme 7. In order to test this
cyanation route, azetidin-3-one 23, previously prepared by
Hanessian and co-workers,11a,21 was reduced to the 3-azetidinol 24
in 93% yield as a single cis isomer (Scheme 8). Azetidin-3-ol 24 was
then converted in a quantitative yield to mesylate 25 and submitted
HO
HO
O
O
N
Ts
OTBDPS
N
H
OH
aspartate analogue
O
N
Ts
N
Ts
16
OTBDPS
OTBDPS
Scheme 4. Strategy for the synthesis of azetidine-derived aspartate analogues from
azetidin-3-one 16.

A.C.B. Burtoloso, C.R.D. Correia / Tetrahedron 64 (2008) 9928–9936
9931
O
1) oxalyl chloride
O
O
DMF, imidazole
TBDPSO
CH2Cl2, 0 °C to r.t., 2h
TBDPSO
HO
TBDPSCl
OH
OH
2) diazomethane,
Et2O, 0 °C to r.t., 1h
N2
15
HNTs
HNTs
90%
HNTs
82%
Cu(acac)2, C6H6,
reflux, 1min.
14
N-tosyl-serine 13
PPh3CH3+Br-
O
O
O
t-BuO-K+, DMSO
PPh3=CH2
TBDPS-OH
or
H
N
Ts
16 72%
OTBDPS
PPh3CH3+Br-
BuLi, THF
30-50%
isolated yield
N
Ts
N
Ts
OTBDPS
OTBDPS
Cp2TiMe2
toluene, 70 °C, 24 h
N
Ts
17 40%
OTBDPS
Scheme 5. Preparation of azetidin-3-one 16 and olefin 17.
C5
C3
HO
OH
.
BH3 SMe2, THF
NaOH, H2O2
OTBDPS
+
N
Ts
17
N
OTBDPS
N
Ts
18
OTBDPS
Ts
50% (3:1)
19
TBAF, THF,
0° C, 3h
HO
O
O
HO
Jones
oxidation
N
Ts
21
OH
N
Ts
20 85%
OH
O
HO
O
O
O
HO
N
Ts
N
Ts
N
Ts
22 60%
Scheme 6. Attempts in the synthesis of diacid 21 from olefin 17.
to cyanation using KCN. Surprisingly, all attempts to form nitrile 26
failed, even under drastic conditions (DMSO, 80 ꢁC, KCN, 7 days).
The starting mesylate 25 is recovered in almost quantitative yields
from these reactions.
substitutions on this type of system. As the carbamate protecting
group in compound 25 makes the formation of the bicyclobuto-
nium difficult, we decided to exchange the Boc for a benzyl group
and reexamine the cyanation reaction. The Boc group of mesylate
25 was then removed with trifluoroacetic acid and the resulting
trifluoroacetate salt 27 was alkylated with benzyl bromide. Next,
the crude N-benzyl-mesylate 28 was reacted with KCN in MeOH
under reflux for 30 min22 furnishing the desired nitrile 29 in 35%
yield after three steps with complete retention of configuration.
Although nitrile 29 could be synthesized in satisfactory yields un-
der these conditions, removal of the TBDPS group with TBAF (74%
yield), followed by the oxidation to the carboxylic acid24 failed to
provide acid 31 (Scheme 8).
Finally, after the above setbacks we found out that the synthesis
of the azetidine-derived aspartate analogue could be performed by
the reduction of the ester function in compound 7 (previously used
in the synthesis of the glutamate analogues) and elimination of the
primary alcohol, followed by the oxidative cleavage of the double
bond (Scheme 9).
Based on the works of Masuda22 and Marchand,23 we realized
that the formation of a bicyclobutonium is a very important step
in the process and constitutes a driving-force for successful
O
CN
HO
O
N
PG
OTBDPS
N
H
OH
aspartate analogue
O
OMs
N
PG
OTBDPS
N
PG
OTBDPS
Therefore, based on a protocol described by Jiang and co-
Scheme 7. Strategy for the synthesis of azetidine-derived aspartate analogues from
cyanation of 3-mesyloxy azetidines.
workers,25 ester 7 was first hydrolyzed with lithium hydroxide,

9932
A.C.B. Burtoloso, C.R.D. Correia / Tetrahedron 64 (2008) 9928–9936
CH2Cl2, Et3N
OMs
CN
KCN, DMSO
80 °C, 7 d
OH
O
DMAP, MsCl,
NaBH4, MeOH
0 °C, 5 min.
0 °C to r.t., 30 min.
N
Boc
N
Boc
98%
OTBDPS
26
OTBDPS
25
N
OTBDPS
24
N
Boc
OTBDPS
23
Boc
single
diastereoisomer 93%
TFA, 5 min,
r.t.
H
OMs
CH3CN, K2CO3, BnBr
-40 °C to r.t., 30 min.
OMs
MeOH, KCN
reflux, 30 min
N
N
H
Bn
OTBDPS
N
CN-
OTBDPS
OTBDPS
bicyclobutonium
H
28
Ph
27
CF3COO
CN
N
CN
CN
Jones and IBX/Pinick
oxidations
O
TBAF, THF
N
N
OH
OH
Ph
30 74%
OTBDPS
29 35% after 3 steps
Scheme 8. Attempted synthesis of azetidine-derived aspartates by cyanation of 3-mesiloxy azetidines.
31
Ph
Ph
azetidine nucleus, employing common intermediates from chiral
(S)-N-tosyl-phenylglycine. The key steps in the synthesis involved
a copper catalyzed N–H insertion of diazoketones to construct the
four-membered rings, a very efficient Wittig olefination of an aze-
tidin-3-one, followed by a highly stereoselective rhodium catalyzed
hydrogenation. Epimerization of the cis glutamate analogue 12
with DBU allows the reported route to be extended to the synthesis
of the trans analogues with good diastereoselectivity.
OH
OEt
1. NaOH, H2O, THF
O
2. a) ClCOOiBu, THF
b) NaBH4, THF:H2O
Ph
32
Ph
N
Ts
N
Ts
7
RuCl3.H2O, NaIO4,
H2O, AcOEt,
CH3CN, 48 h
1. o-NO2PhSeCN
Bu3P, THF, r.t., 1 h.
Ph
2. H2O2, H2O
4. Experimental section
4.1. General procedures
N
Ts
33
53% after 3 steps
HO
O
HO
O
Reagents and solvents are commercial grade and were used as
supplied, except when specified in the experimental procedure. In
the cases where dry solvents were employed, Et3N, CH3CN, DMF,
and CH2Cl2 were distilled from calcium hydride and THF, Et2O,
toluene, and benzene were distilled from Na. Diazomethane was
prepared from diazaldÒ. Unless otherwise noted, reagents and
solvents were added by syringe, and organic extracts were dried by
being stirred over anhydrous Na2SO4, filtered through paper filter
and concentrated under reduced pressure with the aid of a rotary
evaporator. Flash chromatography was carried out by using Merck
60 (230–400 mesh) silica gel. Reactions and chromatography
fractions were analyzed employing precoated silica gel 60 F254
plates (Merck). 1H NMR and 13C NMR data were recorded on
a Varian Gemini 2000 (7.0 T) or Varian Inova (11.7 T) spectrometer.
Chemical shifts are expressed in parts per million downfield from
internal tetramethylsilane and J values are expressed in hertz.
Spectra recorded in D2O were referenced at 4.84 ppm. Gas chro-
matography analyses were carried out in a HP-6890 with a capillar
column HP-5. Electron spray mass spectra were measured in an AP
QTrap-LC/MS instrument. High resolution mass spectra (HRMS)
were measured on a VG Autospec-Micromass spectrometer. IR
spectra were obtained on a Thermo-Nicolet IR-200 spectrometer.
Optical rotations were measured at 24 ꢁC with a Perkin–Elmer 241.
Melting points were measured with a Unimelt-Capilar from
Thomas Hoover and were not corrected.
C10H8, Na, THF
-78 to 0 °C, 1 h
26%, 2 steps
(3 transformations)
O
O
N
Ts
OH
N
H
OH
34
3a
aspartate analogue
[a]D +19 (c 0.24; HCl 0.5M)
(lit. +18, c 0.40; HCl 0.5M)
Scheme 9. Synthesis of aspartate analogue 3a from azetidine ester.
converted to a mixed anhydride and reduced in the presence of
sodium borohydride. Next, the crude alcohol 32 was submitted to
elimination with 2-nitrophenylselenecyanate and hydrogen per-
oxide to furnish olefin 33 in 53% yield after three steps (cis/trans,
92:08). After a single recrystallization from benzene/hexanes the
cis olefin was enriched in more than 98%. The completion of the
synthesis was realized after treatment of olefin 33 with RuCl3 hy-
drate and NaIO4,14 followed by tosyl group removal with Na/
naphthalene in THF.17 After these three transformations (cleavage
of terminal double bond, cleavage of phenyl ring and Ts removal)
the azetidine-derived aspartate analogue 3a was synthesized in
16% overall yield from azetidine 7. The spectroscopic data and the
optical rotation value of 3a are in accordance with the ones
described by Chamberlin and co-workers.26
4.2. (S)-N-(3-Diazo-2-oxo-1-phenylpropyl)-4-methyl-
3. Conclusions
benzenesulfonamide (4)
In summary, we have accomplished the stereoselective syn-
thesis of some glutamate and aspartate analogues, containing an
To a solution of the (S)-N-Ts-2-phenylglycine (1.57 g, 5.0 mmol)
in 25.0 mL of dry CH2Cl2 at 0 ꢁC was added 6.0 mmol of oxalyl

A.C.B. Burtoloso, C.R.D. Correia / Tetrahedron 64 (2008) 9928–9936
9933
chloride, followed by two drops of DMF. After 2 h of stirring at room
temperature, the solvent was evaporated in vacuum and 25.0 mL of
dry THF was added to the pale yellow oil. The resulting solution was
cooled to 0 ꢁC and a freshly prepared solution of the diazoalkane in
ether was added (2 equiv or more). After stirring for 1 h at 0 ꢁC, the
excess of CH2N2 was removed (bubbling argon to the reaction
flask), the solution was then concentrated in vacuum and the crude
product purified by flash column chromatography (30% EtOAc/
hexanes) to furnish 1.06 g (64%) of the diazoketone 4 (the com-
pound can also be purified by recrystallization in benzene/hex-
Rh/C were added and the solution was saturated with H2 for
20 min. After that, the reaction was stirred with a H2 atmosphere
(balloon filled with H2) until the total consumption of the enoate
(2 h). After this period the solution was filtered and the solvent
evaporated, furnishing 90% of cis ester 7 as an inseparable 92:08
isomeric mixture (single homogeneous spot in TLC). 1H NMR
(300 MHz, CDCl3):
d
¼1.08 (t, J¼7.3 Hz, 3H), 2.09 (dd, J¼16.8, 6.6 Hz,
1H), 2.31 (dd, J¼16.8, 9.5 Hz, 1H), 2.47 (s, 3H), 2.90 (m, 1H), 3.52 (dd,
J¼8.1, 3.7 Hz, 1H), 3.82–4.02 (m, 3H), 5.05 (d, J¼8.8 Hz, 1H), 7.22–
7.42 (m, 7H), 7.69 (d, J¼8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3):
anes). 1H NMR (300 MHz, CDCl3):
(s, 1H), 6.16 (d, J¼5.1 Hz, 1H), 7.10–7.30 (m, 7H), 7.53 (d, J¼8.1 Hz,
d
¼2.36 (s, 3H), 4.87 (br s,1H), 5.13
d
¼14.2, 21.7, 30.8, 34.8, 52.8, 60.5, 66.9, 126.8, 128.1, 128.3, 129.6,
131.4, 135.8, 144.0, 171.2; IR (neat, cmꢀ1): 3027, 2982, 2925, 1732,
1593, 1343, 1156, 1095, 1025; HRMS m/z calcd for C20H23NO4S:
373.1348. Found: 373.1276; TLC: Rf¼0.42, 30% EtOAc/hexanes.
2H); 13C NMR (75 MHz, CDCl3):
d
¼21.5, 55.0, 63.5, 126.9, 127.6,
128.5, 128.8, 129.2, 135.6, 136.8, 143.1, 188.8; IR (neat, cmꢀ1): 3265,
3091, 2124, 1627, 1365, 1341, 1166, 725; ESI-MS: 330 (Mþ1), 302,
260, 184, 155, 131, 103, 91; HRMS m/z calcd for C16H15N3O3S:
4.6. (2R,3S)-Methyl 3-(2-ethoxy-2-oxoethyl)-1-tosylazetidine-
329.0834. Found: 329.07301; TLC: Rf¼0.28, 30% EtOAc/hexanes;
2-carboxylate (9)
24
[
a]
þ219.5 (c 2.58, CHCl3); mp: 136–137 ꢁC.
D
Ester 7 (570.0 mg, 1.50 mmol) was dissolved in a 10 mL 1:1
mixture of acetonitrile and ethyl acetate. After that, 10.0 g of so-
dium periodate, dissolved in 40 mL of water, followed by 55.0 mg of
RuCl3 hydrate (35%) was added to the organic solution. The new
solution was then strongly stirred at room temperature for 3 h.
After this period, 40 mL of ethyl acetate was added and the mixture
containing a white precipitate filtered in Celite. The organic and
aqueous phases were separated and the aqueous one extracted
with ethyl acetate (3ꢂ20 mL). The resulted organic phases were
then dried with Na2SO4, filtered, and evaporated. To the resulted oil
were added 10 mL of Et2O, followed by an ethereal solution of
diazomethane until the solution becomes yellow. Next, the solvent
was concentrate and the oil purified by flash column chromato-
graphy (30% EtOAc/hexanes), furnishing 245.4 mg of diester 9 (45%)
as a viscous oil (inseparable mixture of cis and trans isomers,
4.3. (S)-2-Phenyl-1-tosylazetidin-3-one (5)
Diazoketone 4 (1.65 g, 5.0 mmol) was dissolved in 100 mL of
benzene and the yellow solution heated under reflux with a heat
gun with stirring. After that, 10 mol % of Cu(OAc)2$H2O was added
in portions, turning the reaction mixture brown immediately and
liberating nitrogen. CAUTION: liberation of nitrogen is quite violent
and large scale reactions (more than 10 mmol) should be done in big
reaction recipients to permit nitrogen liberation. After 1 min, the re-
action was cooled, the solvent evaporated and the crude product
purified by flash column chromatography (50% CH2Cl2/hexanes) to
furnish 1.05 g (70%) of azetidin-3-one 5 (the compound can also be
purified by recrystallization in benzene/hexanes). 1H NMR
(300 MHz, CDCl3):
d
¼2.45 (s, 3H), 4.61 (dd, J¼16.1, 4.4 Hz, 1H), 4.77
(d, J¼16.1 Hz, 1H), 5.74 (d, J¼4.4 Hz, 1H), 7.00–7.30 (m, 7H), 7.78 (d,
92:08). 1H NMR (300 MHz, CDCl3):
d¼1.22 (t, J¼7.3 Hz, 3H), 2.45 (s,
J¼8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d
¼21.6, 70.2, 86.6, 126.0,
3H), 2.59 (dd, J¼16.8, 9.5 Hz, 1H), 2.65 (dd, J¼16.8, 6.6 Hz, 1H), 3.47
(dd, J¼8.1, 4.4 Hz, 1H), 3.00 (m, 1H), 3.73 (s, 3H), 4.00 (t, J¼8.1 Hz,
1H), 4.09 (q, J¼7.3 Hz, 2H), 4.71 (d, J¼9.5 Hz, 1H), 7.35 (d, J¼8.1 Hz,
128.3, 128.7, 129.9, 131.7, 132.1, 145.0, 193.1; IR (neat, cmꢀ1): 3060,
2974,1814,1336,1152,1091,1001; ESI-MS: 302 (Mþ1), 274,184,155,
119, 91; HRMS m/zcalcd for C16H15NO3S:301.0773. Found: 301.0799;
2H), 7.77 (d, J¼8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3):
¼14.2, 21.6,
d
24
TLC: Rf¼0.46, CHCl3; mp: 163–164 ꢁC; [
a
]
þ272.0 (c 1.05, CHCl3).
27.9, 34.4, 52.3, 53.0, 60.9, 62.5, 128.1, 129.7, 144.1, 168.3, 170.5; IR
(neat, cmꢀ1): 2984, 2950, 2894, 1732, 1441, 1161, 1093, 1037; HRMS
m/z calcd for C14H16NO5S (MꢀEtO): 310.0749. Found: 310.1006;
TLC: Rf¼0.25, 30% EtOAc/hexanes; trans isomer: 1H NMR (300 MHz,
D
4.4. (S)-Ethyl 2-(2-phenyl-1-tosylazetidin-3-ylidene)
acetate (6)
CDCl3):
d
¼1.22 (t, J¼7.3 Hz, 3H), 2.39 (dd, J¼16.1, 6.6 Hz, 1H), 2.45 (s,
Azetidin-3-one 5 (1.82 g, 6.05 mmol) was dissolved in 120 mL of
benzene. Next, 2.32 g (6.65 mmol, 1.1 equiv) of the stabilized ylide
was added to this solution, which was stirred for 1 h under reflux.
After this time, the solution was cooled to room temperature and
the solvent evaporated. The resulted oil was then dissolved in a 1:1
mixture of ethyl acetate and hexanes and the suspension filtered in
flash column chromatography silica (to remove triphenyl phos-
phine oxide). After this purification, 2.21 g (99% yield) of enoate 6
was obtained as E and Z mixture of isomers (oil becomes solid with
3H), 2.51 (dd, J¼16.1, 6.6 Hz, 1H), 3.02 (sext, J¼7.3 Hz, 1H), 3.59 (t,
J¼7.3 Hz, 1H), 3.71 (s, 3H), 3.91 (t, J¼7.3 Hz, 1H), 4.08 (q, J¼7.3 Hz,
2H), 4.30 (d, J¼7.3 Hz, 1H), 7.34 (d, J¼8.8 Hz, 2H), 7.77 (d, J¼8.8 Hz,
2H); TLC: Rf¼0.25, 30% EtOAc/hexanes.
4.7. (2R,3S)-3-(Carboxymethyl)-1-tosylazetidine-2-carboxylic
acid (10)
Diester 9 (227.5 mg, 0.64 mmol) was dissolved in 7.0 mL of THF.
Next, 7.0 mL of a 2 M aqueous solution of LiOH was added and the
solution stirred for 12 h at room temperature. After this period,
a 2 M aqueous HCl solution was added to the reaction solution
(until pH 1) and the aqueous phase extracted with ethyl acetate
(3ꢂ20 mL). The organic phase was then dried with Na2SO4, filtered,
and evaporated, furnishing 178 mg of diacid 10 (90% yield) as
a white solid (mixture of isomers, 92:08). Next, diacid 10 was dis-
solved in a minimum amount of EtOH, followed by a slow addition
of hexanes and slow freezing. After this recrystallization procedure,
cis diacid was enriched in more than 98%. 1H NMR (300 MHz, ac-
time). 1H NMR (300 MHz, CDCl3), major isomer:
d¼1.23 (t, J¼7.3 Hz,
3H), 2.43 (s, 3H), 4.11 (q, J¼7.3 Hz, 2H), 4.71 (dt, J¼16.1, 2.9 Hz, 1H),
4.84 (ddd, J¼16.1, 4.4, 2.9 Hz, 1H), 5.52–5.59 (m, 2H), 7.30–7.42 (m,
7H), 7.73 (d, J¼8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3), major isomer:
d
¼14.2, 21.6, 58.7, 60.6, 73.3, 114.6, 126.7, 128.2, 128.6, 129.7, 132.0,
136.4, 144.2, 154.0, 164.7; IR (neat, cmꢀ1): 3059, 3033, 2976, 1720,
1705, 1346, 1199, 1158, 1086; HRMS m/z calcd for C20H21NO4S:
371.1191. Found: 371.1177; TLC, major isomer: Rf¼0.50, 30% EtOAc/
hexanes.
4.5. Ethyl 2-((2R,3S)-2-phenyl-1-tosylazetidin-3-yl) acetate (7)
etone-d6):
d
¼2.46 (s, 3H), 2.67 (d, J¼8.1 Hz, 2H), 2.97 (m, 1H), 3.50
(dd, J¼8.1, 4.4 Hz, 1H), 3.90 (t, J¼8.1 Hz, 1H), 4.62 (d, J¼9.5 Hz, 1H),
Enoate 6 (EþZ) (620.0 mg, 1.67 mmol) was dissolved in a mini-
7.49 (d, J¼8.8 Hz, 2H), 7.79 (d, J¼8.8 Hz, 2H); 13C NMR (75 MHz,
mum amount of benzene. Then, 55 mL of MeOH and 172.0 mg of 5%
acetone-d6):
d¼21.6, 28.4, 34.5, 54.2, 63.8, 129.0, 130.8, 134.1, 145.1,

9934
A.C.B. Burtoloso, C.R.D. Correia / Tetrahedron 64 (2008) 9928–9936
169.6, 172.5; IR (neat, cmꢀ1): 3300–2500, 1698, 1437, 1346, 1229,
4.11. ((2R,3S)-2-((tert-Butyldiphenylsilyloxy)methyl)-1-
1161, 943; HRMS m/z calcd for C132H4 15NO6S: 313.0620. Found:
tosylazetidin-3-yl)methanol (18)
313.0590; mp: 201–202 ꢁC (dec); [
1.28, acetone).
a
]
þ1.6 (c 2.44, THF), þ3.9 (c
D
Olefin 17 (281.0 mg, 0.57 mmol) was dissolved in 5.7 mL of dry
THF and the solution cooled to 0 ꢁC. Next, 65
mL of BH3$SMe com-
4.8. (2R,3S)-3-(Carboxymethyl)azetidine-2-carboxylic
acid (11)
plex was added and the reaction stirred for 2 h at room tempera-
ture. The solution was then cooled to 0 ꢁC, followed by the addition
of 0.4 mL of a 3 M aqueous NaOH solution and 0.4 mL of 30%
aqueous H2O2 solution. After stirring for 1 h at room temperature,
H2O was added to the reaction flask and the product extracted with
EtOAc (3ꢂ20 mL). The organic phase was dried over Na2SO4, fil-
tered, and evaporated to furnish the crude alcohol 18, which was
purified by flash column chromatography (50% EtOAc/hexanes) to
Diacid 10 (30.0 mg, 0.096 mmol) was dissolved in 2.0 mL of dry
THF and the suspension cooled to ꢀ78 ꢁC. Next, a 0.8 M solution of
Na/naphthalene radical anion in THF (2.5 mL, 20 equiv) was added
to the reaction. The dark green solution was then stirred at 0 ꢁC for
2 h and, after this period, H2O was added until the disappearance of
the dark green color. Next, the aqueous phase was washed with
Et2O (2ꢂ10 mL), acidified with a 2.0 M HCl aqueous solution and
evaporated. The residue was then purified by ion-exchange resin
(Dowex Hþ 50) and the obtained solid redissolved in H2O. After
filtration, the aqueous solution was evaporated to furnish 14.7 mg
(97%) of the desired amino acid as a opaque colorless solid. 1H NMR
provide 150.0 mg (50%) of
regioisomers 18 and 19 in a 3:1 ratio. Compound 18: 1H NMR
(300 MHz, CDCl3):
a separable mixture of the two
d
¼1.05 (s, 9H), 2.41 (s, 3H), 2.60 (m, 1H), 3.36
(dd, J¼8.4, 4.2 Hz,1H), 3.54 (t, J¼8.4 Hz,1H), 3.63 (dd, J¼11.7, 4.2 Hz,
1H), 3.76–3.87 (m, 1H), 3.92 (dd, J¼11.1, 4.8 Hz, 1H), 4.17 (2t,
J¼11.1 Hz, 2H), 7.20–7.75 (14H, Ar); 13C NMR (75 MHz, CDCl3):
(300 MHz, D2O):
d
¼2.44 (dd, J¼16.1, 11.7 Hz, 1H), 2.60 (dd, J¼16.1,
d
¼19.0, 21.6, 26.7, 33.6, 60.9, 62.2, 63.0, 127.5, 127.7, 129.4, 129.9,
5.1 Hz, 1H), 3.40 (m, 1H), 3.77 (dd, J¼10.9, 6.6 Hz, 1H), 4.30 (dd,
135.2, 135.3, 143.8; IR (neat, cmꢀ1): 3481, 3086, 2955, 2928, 2856,
J¼10.9, 8.8 Hz, 1H), 4.90 (d, J¼9.5 Hz, 1H); 13C NMR (75 MHz, D2O):
1597, 1428, 1347, 1160, 1106, 820, 742, 704; ESI-MS: 510 (Mþ1), 432,
d
¼30.5, 34.5, 48.5, 61.8, 170.6, 176.0; IR (cmꢀ1): 3077, 1679, 1625,
354, 254, 236, 155, 83; HRMS m/z calcd for C24H26NO4SSi (Mꢀt-Bu):
24
1574, 1421, 1184, 1129, 974, 801, 723; ESI-MS: 160 (Mþ1), 114, 97, 96,
452.1351. Found: 452.1464; TLC: Rf¼0.46, 50% EtOAc/hexanes; [
a]
D
84, 78, 68; HRMS m/z calcd for C6H9NO4: 159.0532. Found:
þ102.9 (c 0.95, CHCl3). Compound 19: 1H NMR (300 MHz, CDCl3):
24
159.0618; [
ORD).
a
]
ꢀ4.8 (c 0.30, H2O) (optical rotatory dispersion,
d
¼1.05 (s, 9H), 1.53 (s, 3H), 2.43 (s, 3H), 3.32 (d, J¼7.8 Hz, 1H), 3.53
D
(d, J¼7.8 Hz, 1H), 3.57 (dd, J¼9.3, 4.8 Hz, 1H), 3.86 (dd, J¼10.5,
9.3 Hz, 1H), 3.95 (dd, J¼10.5, 4.8 Hz, 1H), 7.20–7.80 (14H, Ar); 13C
4.9. (2R,3S)-Methyl-3-((methoxycarbonyl)methyl)-1-
tosylazetidine-2-carboxylate (12)
NMR (75 MHz, CDCl3):
d
¼19.3, 21.6, 21.7, 26.9, 62.5, 62.6, 69.8, 73.4,
127.7, 128.3, 129.6, 129.7, 132.8, 133.0, 135.4, 143.9; IR (neat, cmꢀ1):
3518, 3072, 2933, 2915, 2857, 1593, 1428, 1341, 1327, 1151, 1107,
1086, 704; ESI-MS: 510 (Mþ1), 432, 279, 275, 149; HRMS m/z calcd
Diacid 10 (10.0 mg, 0.032 mmol) was dissolved in 1.0 mL of a 2:1
mixture of benzene/methanol at room temperature. Next, a 2.0 M
solution of TMSCHN2 in hexanes was added dropwise until a yellow
color persisted. After stirring for 30 min the solution was quenched
by dropwise addition of acetic acid and evaporated, to furnish di-
for
C
24H26NO4SSi (Mꢀt-Bu): 452.1351. Found: 452.1374; TLC:
24
Rf¼0.49, 50% EtOAc/hexanes; [
a]
þ86.8 (c 2.13, CHCl3).
D
4.12. ((2R,3S)-1-Tosylazetidine-2,3-diyl)dimethanol (20)
ester 12 in quantitative yield. 1H NMR (250 MHz, CDCl3):
d
¼2.44 (s,
3H), 2.61–2.65 (m, 2H), 2.98 (m, 1H), 3.46 (dd, J¼8.0, 4.0 Hz, 1H),
3.63 (s, 1H), 3.72 (s, 1H), 3.99 (t, J¼8.3 Hz,1H), 4.69 (d, J¼9.0 Hz,1H),
7.35 (d, J¼8.0 Hz, 2H), 7.77 (d, J¼8.0 Hz, 2H); 13C NMR (62.5 MHz,
Alcohol 18 (100.0 mg, 0.2 mmol) was dissolved in 2.0 mL of THF
and the solution cooled to 0 ꢁC. Next, 0.3 mL (0.3 mmol) of a 1 M
solution of TBAF was added and the reaction stirred for 3 h at room
temperature. After that, the solvent was evaporated and the residue
purified by flash column chromatography (60% EtOAc/hexanes), to
CDCl3):
d
¼21.6, 27.8, 34.1, 51.9, 52.3, 52.9, 62.5, 128.3, 129.8, 132.9,
144.4, 168.6, 171.3; IR (neat, cmꢀ1): 3033, 2993, 2954, 2895, 1734,
1597, 1441, 1340, 1209, 1157, 1099; ESI-HRMS m/z calcd for
furnish 45.0 mg of diol 20 (85%). 1H NMR (300 MHz, CDCl3):
d¼2.47
24
C
15H19NO6SHþ: 342.1011. Found: 342.1018; [
a
]
þ20.0 (c 1.25,
(s, 3H), 2.50 (m, 1H), 3.50 (dd, J¼8.4, 4.0 Hz, 1H), 3.57 (t, J¼8.4 Hz,
1H), 3.76 (dd, J¼11.7, 5.1 Hz, 1H), 3.83–4.08 (m, 4H), 7.39 (d,
J¼7.8 Hz, 2H), 7.72 (d, J¼7.8 Hz, 2H); 13C NMR (75 MHz, CDCl3):
D
CHCl3).
4.10. (R)-2-((tert-Butyldiphenylsilyloxy)methyl)-3-
methylene-1-tosylazetidine (17)
d
¼21.6, 33.3, 49.8, 60.7, 61.2, 65.1, 128.1, 129.6, 130.6, 144.1; IR (neat,
cmꢀ1): 3387, 3068, 2954, 2929, 2856, 1467, 1429, 1338, 1159, 1111,
1043, 854, 820, 704; ESI-HRMS m/z calcd for C12H17NO4SHþ:
272.0957. Found: 272.0961; [
24
Azetidine-3-one 16 (65.2 mg, 0.13 mmol) (see Ref. 7c for ex-
perimental details) was dissolved in 0.9 mL of a 0.5 M solution of
Petasis reagent (Cp2TiMe2) in toluene (0.45 mmol) and the new
solution stirred and heated at 70–80 ꢁC for 24 h in the absence of
light. After this period, hexane was added in the reaction flask and
the mixture filtered in a short pad of silica. The solvent was then
evaporated and the crude material purified by flash column chro-
matography (20% Et2O/hexanes) to provide 25.1 mg (40%) of olefin
a
]
þ25.0 (c 0.30, CHCl3).
D
4.13. (1S,5R)-6-Tosyl-3-oxa-6-azabicyclo[3.2.0]heptan-2-
one (22)
Diol 20 (22.0 mg, 0.08 mmol) was dissolved in 2.0 mL of acetone
and the solution cooled to 0 ꢁC. A solution of Jones’ reagent was
then added to the cooled solution dropwise, until the brown color
persisted. After that, the bath was removed and the reaction stirred
for 30 min. Isopropanol was added to the flask, the mixture filtered
in a short pad of Celite, the solvent dried over Na2SO4, filtered, and
evaporated. Flash column purification of the crude material in 60%
EtOAc/hexanes provided 12.8 mg (60%) of the lactone 22. 1H NMR
17. 1H NMR (300 MHz, CDCl3):
J¼5.4 Hz, 2H), 4.24 (dq, J¼12.6, 2.7 Hz, 1H), 4.34 (dq, J¼12.6, 2.7 Hz,
1H), 4.50 (m, 1H), 4.93 (m, 1H), 5.08 (m, 1H), 7.20–7.75 (Ar, 14H); 13
NMR (75 MHz, CDCl3):
d
¼1.05 (s, 9H), 2.41 (s, 3H), 3.90 (d,
C
d
¼19.4, 21.7, 26.9, 57.8, 65.3, 71.7, 108.2,
127.6, 128.1, 129.6 (2C), 133.0, 133.2, 135.5, 138.2, 143.8; IR (neat,
cmꢀ1): 3072, 3043, 2930, 2657, 1601, 1428, 1348, 1163, 1111, 1092,
703; ESI-MS: 492 (Mþ1), 414, 337, 236, 155, 75; HRMS m/z calcd for
(300 MHz, CDCl3):
d
¼2.47 (s, 3H), 3.07 (ddd, J¼9.0, 6.6, 2.6 Hz, 1H),
3.80 (dd, J¼9.0, 2.6 Hz, 1H), 3.98 (t, J¼9.0 Hz, 1H), 4.33 (dd, J¼11.6,
C
28H33NO3SSi: 491.1950. Found: 491.2043; TLC: Rf¼0.38, 20%
3.9 Hz, 1H), 4.54 (d, J¼11.6 Hz, 1H), 4.78 (dd, J¼6.5, 3.9 Hz, 1H); 13
C
24
EtOAc/hexanes; [
a
]
þ68.1 (c 1.35, CHCl3).
NMR (75 MHz, CDCl3):
d¼21.7, 33.1, 52.3, 63.2, 73.0, 127.9, 128.0,
D

A.C.B. Burtoloso, C.R.D. Correia / Tetrahedron 64 (2008) 9928–9936
9935
129.7, 130.0, 144.8, 176.0; IR (neat, cmꢀ1): 2958, 2918, 2844, 1777,
Et2O. The organic phase was then washed with H2O (2ꢂ30 mL),
dried over Na2SO4, filtered, and evaporated. Flash column chro-
matography purification (30% EtOAc/hexanes) furnished 259.3 mg
of nitrile 32 (34% after three steps). 1H NMR (300 MHz, CDCl3):
1597, 1343, 1160, 1104, 1054, 972; ESI-MS: 268 (Mþ1), 184, 155, 119,
91; HRMS m/z calcd for C12H13NO4S: 267.0565. Found: 267.0580;
24
TLC: Rf¼0.38, 60% EtOAc/hexanes; [
a
]
þ100.0 (c 0.32, CHCl3).
D
d
¼1.07 (s, 9H), 3.07 (t, J¼7.7 Hz, 1H), 3.24 (td, J¼7.7, 3.1 Hz 1H),
4.14. (2S,3S)-tert-Butyl 2-((tert-butyldiphenylsilyloxy)-
methyl)-3-hydroxyazetidine-1-carboxylate (24)
3.42–3.52 (m, 3H), 3.68 (dd, J¼11.0, 6.2 Hz, 1H), 3.74 (d, J¼12.4 Hz,
1H), 3.85 (dd, J¼11.0, 6.2 Hz, 1H), 7.20 (m, 5H), 7.40 (m, 6H), 7.70 (m,
4H); 13C NMR (125 MHz, CDCl3):
d
¼19.1, 23.3, 26.7, 53.6, 61.6, 64.8,
To a solution of 887.4 mg (2.02 mmol) of 3-azetidinone 23 in
20.0 mL of methanol at 0 ꢁC was added 94.0 mg (2.53 mmol) of
NaBH4 and the reaction stirred at this temperature for 5 min. After
this period, a 10% aqueous solution of citric acid was added to the
reaction (until pH 3.0), which was stirred for 5 min. The methanol
was then removed and the aqueous phase extracted with CH2Cl2
(3ꢂ30 mL). After drying over Na2SO4, the organic phase was filtered
and evaporated to provide 823.7 mg (93%) of the alcohol 24 as
65.9, 119.6, 127.3, 127.7, 128.3, 128.6, 129.8, 133.2, 135.6, 136.8; IR
(neat, cmꢀ1): 3077, 2930, 2856, 2239, 1471, 1427, 1110, 823, 740,
701; ESI-MS: 441 (Mþ1), 363, 310, 185, 91; HRMS m/z calcd for
C
28H32N2OSi: 440.2284. Found: 440.2301; TLC: Rf¼0.34, 20% EtOAc/
24
hexanes; [
a
]
þ28.0 (c 1.28, CHCl3).
D
4.17. (2R,3S)-1-Benzyl-2-(hydroxymethyl)azetidine-3-
carbonitrile (30)
a single cis diastereoisomer. 1H NMR (300 MHz, C6D6, 70 ꢁC):
(s, 9H), 1.40 (s, 9H), 3.60 (m, 1H), 3.80–3.90 (m, 2H), 3.95–4.10 (m,
2H), 4.30 (m, 2H), 7.20 (m, 6H), 7.75 (m, 4H); 13C NMR (75 MHz,
d¼1.10
Nitrile 29 (212.0 mg, 0.48 mmol) was dissolved in 5.0 mL of THF
and the solution cooled to 0 ꢁC 0.63 mL (0.63 mmol) of a 1 M so-
lution of TBAF was added and the reaction stirred for 30 min at
room temperature. Next, the solvent was evaporated and the resi-
due purified by flash column chromatography (60% EtOAc/hex-
anes), to furnish 74% of alcohol 30. 1H NMR (300 MHz, CDCl3):
C6D6, 70 ꢁC):
d
¼19.4, 27.1, 28.6, 60.0, 62.9, 65.1, 67.2, 78.8, 127.5,
127.8, 127.9, 128.0, 129.9, 132.8, 133.3, 135.6, 135.9, 155.1; IR (neat,
cmꢀ1): 3469, 3077, 3052, 2962, 2931, 2852, 1700, 1678, 1427, 1107,
702; ESI-MS: 442 (Mþ1), 342, 308, 264, 186; HRMS m/z calcd for
C
21H26NO3Si (Mꢀt-BuO): 368.1682. Found: 368.1592; TLC: Rf¼0.36,
d
¼3.22 (dd, J¼8.7, 7.5 Hz, 1H), 3.27–3.38 (m, 1H), 3.52–3.72 (m, 6H),
24
30% EtOAc/hexanes; [
a
]
þ34.0 (c 1.16, CHCl3).
D
7.30 (m, 5H); 13C NMR (75 MHz, CDCl3):
d
¼22.8, 53.7, 61.5, 62.5,
65.9, 119.4, 127.6, 128.5 (2C), 128.7, 136.6; IR (neat, cmꢀ1): 3408,
3066, 2954, 2933, 2858, 2247, 1466, 1427, 1363, 1111, 1039, 850, 821;
4.15. (2S,3S)-tert-Butyl-2-((tert-butyldiphenylsilyloxy)-
methyl)-3-(methylsulfonyloxy)azetidine-1-carboxylate (25)
ESI-MS: 203 (Mþ1), 91; ESI-HRMS m/z calcd for C12H14N2OHþ:
24
203.1184. Found: 203.1188; [
a
]
þ9.0 (c 1.55, CHCl3).
D
Alcohol 24 (794.0 mg, 1.80 mmol) was dissolved in 18 mL dry
CH2Cl2, followed by the addition of 1.30 mL (9.00 mmol, 5 equiv) of
triethylamine and catalytic DMAP (some crystals). The solution was
then cooled to 0 ꢁC and 0.21 mL (2.70 mmol, 1.5 equiv) of distilled
mesyl chloride (MsCl) added dropwise. The bath was removed and
the reaction stirred at room temperature for 1 h. In the work up,
25 mL of CH2Cl2 was added and the mixture filtered over silica gel.
The silica was washed with 50% EtOAc/CH2Cl2 and the two organic
phases grouped. Evaporation furnished 916.0 mg of the pure
mesylate 25 as a colorless oil (98%). 1H NMR (300 MHz, CDCl3):
4.18. (2R,3S)-2-Phenyl-1-tosyl-3-vinylazetidine (33)
Ester 7 (448.6 mg, 1.2 mmol) was dissolved in 12.0 mL of THF.
Followed by the addition of 12.0 mL of an aqueous LiOH 2 M so-
lution, the mixture was kept under stirring for 12 h and, after that,
the aqueous phase was washed with Et2O. The organic phase was
then acidified with NaHSO4 (until pH 2.0) and extracted with EtOAc
(3ꢂ30 mL). After evaporation of the organic phase, the crude oil
was dried and dissolved in 6.0 mL of dry THF. To this new solution,
d
¼1.08 (s, 9H), 1.39 (s, 9H), 2.90 (s, 3H), 3.94 (dd, J¼10.8, 2.4 Hz, 1H),
4.04–4.33 (m, 3H), 4.50 (td, J¼6.6, 2.1 Hz, 1H), 5.37 (dt, J¼7.0, 5.1 Hz,
at ꢀ21 ꢁC, were added 230
mL of triethylamine (1.4 equiv) and
190 mL of isobutyl cloroformate (1.2 equiv). After stirring for 30 min,
1H), 7.30–7.53 (m, 6H), 7.64–7.82 (m, 4H); 13C NMR (75 MHz,
CDCl3):
d
¼19.3, 26.9, 28.4, 38.2, 56.2, 59.9, 66.7, 68.3, 80.2, 127.6
the solution was filtered quickly (removal of the ammonium hy-
drochloride), added to a solution of NaBH4 (180 mg) in H2O (3.0 mL)
and stirred for 16 h. After this time, the solution was extracted with
Et2O (4ꢂ20 mL), dried with Na2SO4, and evaporated. The crude
primary alcohol 32 was then dried in vacuum and used in the
elimination step directly. For this step, the crude alcohol 32 was
dissolved in 6.0 mL of dry THF, followed by the addition of 545.0 mg
(2.0 equiv) of o-NO2-PhSeCN. Next, the solution was cooled to 0 ꢁC
and 0.5 mL of Bu3P added. After stirring for 1 h at room tempera-
ture, 3.0 mL of a 30% aqueous solution of H2O2 was added and the
mixture stirred for more 3 h. The suspension was then extracted
with CH2Cl2 and the organic phase dried with Na2SO4, filtered, and
evaporated to furnish a yellow solid, which was purified by flash
column chromatography (50% CHCl3/hexanes). After this purifica-
tion, 197.8 mg of the terminal olefin was furnished (53% after three
steps) as a inseparable 90:10 cis/trans isomeric mixture (a single
recrystallization in benzene/hexanes raised the proportion of the
(2C), 129.6, 129.7, 132.9, 133.0, 135.4, 155.0; IR (neat, cmꢀ1): 3072,
3048, 2933, 2889, 2858, 1702, 1365, 1179, 1180, 1112, 964, 860, 703;
ESI-MS: 520 (Mþ1), 420, 386, 342, 246, 197; HRMS m/z calcd for
C
22H28NO5SSi (Mꢀt-BuO): 446.1458. Found: 446.1511; TLC:
24
Rf¼0.40, 30% EtOAc/hexanes; [
a]
þ25.1 (c 0.49, CHCl3).
D
4.16. (2R,3S)-1-Benzyl-2-((tert-butyldiphenylsilyloxy)-
methyl)azetidine-3-carbonitrile (29)
Mesylate 25 (914.6 mg, 1.76 mmol) was dissolved in 1.80 mL of
trifluoroacetic acid and the solution stirred for 5 min at room
temperature. After that, all the solvent was evaporated and the dry
salt 27 [1H NMR (300 MHz, CDCl3):
d¼1.08 (s, 9H), 2.93 (s, 3H), 4.04
(dd, J¼10.0, 5.0 Hz, 1H), 4.15 (dd, J¼10.0, 5.0 Hz, 1H), 4.34 (m, 2H),
4.70 (m, 1H), 4.56 (m, 1H), 7.3–7.8 (m, 10H)] dissolved in dry ace-
tonitrile. The solution was then cooled to ꢀ40 ꢁC, followed by the
addition of anhydrous K2CO3 (730 mg) and benzyl bromide
(0.23 mL, 1.94 mmol). After stirring for 30 min at room tempera-
ture, the mixture was filtered (removal of K2CO3) and the organic
phase evaporated. To the resulting crude benzylated azetidine 28 in
18.0 mL of methanol was added 400.0 mg (6.16 mmol) of KCN and
the reaction stirred under reflux for 30 min. After that, the solvent
was evaporated to dryness and the residue dissolved in 60 mL of
cis isomer in more than 98%). 1H NMR (300 MHz, CDCl3):
d¼2.45 (s,
3H), 3.10 (dddd, J¼8.4, 8.7, 9.0, 4.2 Hz, 1H), 3.66 (dd, J¼8.4, 4.2 Hz,
1H), 3.96 (t, J¼8.4 Hz,1H), 4.89 (d, J¼16.2 Hz,1H), 4.91 (d, J¼11.4 Hz,
1H), 5.08 (d, J¼8.7 Hz, 1H), 5.55 (ddd, J¼16.2, 11.4, 9.0 Hz, 1H), 7.20–
7.80 (9H, Ar); 13C NMR (75 MHz, CDCl3):
117.8, 126.8, 127.6, 128.1, 128.4, 129.7, 131.9, 135.4, 136.6, 144.0; IR
(neat, cmꢀ1): 3085, 2974, 2880, 1601, 1340, 1156, 1091, 911, 751;
d
¼21.5, 38.5, 52.4, 68.4,

9936
A.C.B. Burtoloso, C.R.D. Correia / Tetrahedron 64 (2008) 9928–9936
3. (a) Daw, N. W.; Stein, P. S.; Fox, K. A. Rev. Neurosci. 1993, 16, 207; (b) Colling-
ridge, G. L.; Bliss, T. V. P. Trends Neurosci. 1995, 18, 54; (c) Cotman, C. W.; Kahle,
J. S.; Miller, S. E.; Ulas, J.; Bridges, R. J. Excitatory Amino Acid Neurotransmission.
In Psychopharmacology: The Fourth Generation of Progress; Bloom, F. E., Kupfer,
D. J., Eds.; Raven: New York, NY, 1995; p 75.
HRMS m/z calcd for C18H19NO2S: 313.1137. Found: 313.1170; TLC:
24
Rf¼0.45, 30% EtOAc/hexanes; [
a
]
þ262.6 (c 1.74, CH2Cl2).
D
4.19. (2R,3S)-Azetidine-2,3-dicarboxylic acid (3a)
4. (a) Choi, D. W. Annu. Rev. Neurosci. 1990, 13, 171; (b) Meldrum, B. S. Brain Pathol.
1993, 3, 405; (c) Choi, D. W. Prog. Brain Res. 1994, 100, 47; (d) Rothman, S. M.;
Olney, J. W. Trends Neurosci. 1995, 18, 57.
5. Chamberlin, A. R.; Bridges, R. J. Conformationally Constrained Amino Acids
as Probes of Glutamate Receptors and Transporters. In Drug Design for
Neuroscience; Kozikowski, A. P., Ed.; Raven: New York, NY, 1993; pp 231–
259.
To a solution of 85.0 mg (0.27 mmol) of olefin 36 in 6.0 mL of
a 1:1 mixture of ethyl acetate and acetonitrile was added 10.0 mL of
an aqueous solution of NaIO4 (1.75 g). After that, 10.0 mg of 35%
RuCl3 hydrate was added and the mixture was vigorously stirred for
1 h. A gray salt was precipitated after this period and a TLC analysis
revealed the complete disappearance of the terminal olefin and the
formation of two new compounds (mono and diacid). After this
analysis, more 4.0 mL of H2O and 5.0 mg of the ruthenium catalyst
were added every 12 h of reaction, until the total conversion of the
monoacid to the diacid 34 was observed (48 h by TLC). EtOAc
(20 mL) was then added to the reaction vessel and the mixture
filtered in Celite. The two phases were separated and the aqueous
phase extracted 3ꢂ with EtOAc. All the organic phases were
grouped, dried with Na2SO4, and evaporated to furnish the crude
diacid 34. Next, to the crude diacid in 2.0 mL of dry THF at ꢀ78 ꢁC
(suspension), a solution of Na/naphthalene radical anion in THF was
added until the dark green color persisted in the reaction. The so-
lution was then stirred at 0 ꢁC for 1 h and, after this period, H2O was
added until the disappearance of the dark green color. Next, the
aqueous phase was acidified with a 2.0 M HCl aqueous solution and
washed with Et2O for naphthalene removal. The aqueous phase
was evaporated to dryness and the residue purified by ion-ex-
change resin (Dowex Hþ 50) and recrystallized with ethanol. The
azetidine amino acid 3a was obtained in 26% (10.0 mg) after the
three transformations, as an opaque solid. 1H NMR (300 MHz, D2O):
6. (a) Kozikowski, A. P.; Tu¨ckmantel, W.; Reynolds, I. J.; Wroblewski, T. J. J. Med.
Chem. 1990, 33, 1561; (b) Kozikowski, A. P.; Tu¨ckmantel, W.; Liao, Y.; Wro-
blewski, T. J.; Wang, S.; Pshenichkin, S.; Surin, A.; Thomsen, C. Bioorg. Med.
Chem. Lett. 1996, 6, 2559; (c) Kozikowski, A. P.; Tu¨ckmantel, W.; Liao, Y.; Wro-
blewski, T. J.; Manev, H.; Ikonomovic, S. J. Med. Chem. 1993, 36, 2706; (d)
Bridges, R. J.; Lovering, F. E.; Humphrey, J. M.; Stanley, M. S.; Blakely, T. N.;
Cristofaro, M. F.; Chamberlin, R. Bioorg. Med. Chem. Lett. 1993, 3, 115; (e) Ara-
kawa, Y.; Murakami, T.; Arakawa, Y.; Yoshifugi, S. Chem. Pharm. Bull. 2003, 51,
96; (f) De Kimpe, N.; Boeykens, M. Tetrahedron 1998, 54, 2619; (g) Hanessian, S.;
Bernstein, N.; Yang, R.; Maguire, R. Bioorg. Med. Chem. Lett. 1999, 9, 1437; (h)
Couty, F.; Evano, G.; Rabasso, N. Tetrahedron: Asymmetry 2003, 14, 2407; (i)
Couty, F.; Carlin-Sinclair, A.; Rabasso, N. Synlett 2003, 726; (j) Enders, D.; Gries,
J. Synthesis-Stuttgart 2005, 20, 3508; (k) Kiss, L.; Mangelinckx, S.; Fu¨ lo¨p, F.;
DeKimpe, N. Org. Lett. 2007, 9, 4399; (l) Sivaprakasham, M.; Couty, F.; Evano, G.;
Srinivas, B.; Sridhar, R.; Rao, K. R. Arkivoc 2007, 10, 71; (m) Gerona-Navarro, G.;
Angeles Bonache, M.; Alı´as, M.; Pe´rez de Vega, M. J.; Garcı´a-Lo´pez, T.; Pilar
Lo´ pez, M.; Cativiela, C.; Gonza´lez-Mun˜iz, R. Tetrahedron Lett. 2004, 45, 2193; (n)
Brau¨ner-Osborne, H.; Bunch, L.; Chopin, N.; Couty, F.; Evano, G.; Jensen, A. A.;
Kusk, M.; Nielsen, B.; Rabasso, N. Org. Biomol. Chem. 2005, 3, 3926; (o) Couty, F.;
Evano, G. Org. Prep. Proced. Int. 2006, 427.
7. (a) Burtoloso, A. C. B.; Correia, C. R. D. Synlett 2005, 1559; (b) Burtoloso, A. C. B.;
Correia, C. R. D. Tetrahedron Lett. 2004, 45, 3355; (c) Burtoloso, A. C. B.; Correia,
C. R. D. J. Organomet. Chem. 2005, 690, 5636.
8. For a review on azetidin-3-ones, see: Dejaegher, Y.; Kuz’nenok, N. M.; Zvonok,
A. M.; De Kimpe, N. Chem. Rev. 2002, 102, 29.
9. Compound 4 was also prepared by Pusino: Pusino, A.; Saba, A.; Desole, G. Gazz.
Chim. Ital. 1985, 115, 33.
10. For the synthesis of N-tosyl-azetidin-3-ones employing Cu(acac)2, see: Wang,
J.; Hou, Y.; Wu, P. J. Chem. Soc., Perkin Trans. 1 1999, 2277.
d
¼3.74 (m, 1H), 4.06 (dd, J¼10.5, 5.4 Hz, 1H), 4.25 (dd, J¼10.5,
9.0 Hz, 1H), 5.02 (d, J¼10.0 Hz, 1H); 13C NMR (75 MHz, D2O):
¼41.1,
24
d
11. For previous applications of the Wittig olefination of azetidin-3-ones, see: (a)
Hanessian, S.; Fu, J.; Chiara, J. L.; Di Fabio, R. Tetrahedron Lett. 1993, 34, 4157; (b)
Podlech, J.; Seebach, D. Helv. Chim. Acta 1995, 78, 1238; (c) Emmer, G. Tetrahe-
dron 1992, 48, 7165.
45.7, 60.7, 171.5, 175.8; IR (neat, cmꢀ1): 3037, 1575, 1402, 1311; [
a]
D
þ19.3 (c 0.24, HCl 0.5 M in H2O) (lit: þ18 (c 0.40, HCl 0.5 M in H2O)).
12. Liu, H.; Ramani, B. Synth. Commun. 1985, 15, 965.
13. The cis compound 6 could not be separated from its trans isomer by column
chromatography.
Acknowledgements
14. Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1992, 33, 7921.
15. The use of diazomethane was merely to facilitate isolation and purification of 9.
Compound 9 was obtained as an inseparable mixture of the cis and trans
stereoisomers.
16. Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 58, 4727.
17. (a) Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett. 1999, 40, 6181; (b) Closson, W.
D.; Ji, S.; Schulenberg, S. J. Am. Chem. Soc. 1970, 92, 650.
18. In some occasions, a small amount of epimerization at C2 was observed.
19. Attempts to carry out this epimerization step beyond the cis/trans ratio of 20:
80 were fruitless. As a typical procedure, 0.10 mmol of compound 12 is dis-
solved in 3.0 mL of dry toluene. After that, 10 equiv of pure DBU is added and
the solution stirred under reflux for 7 h. After cooling, the solution is filtered in
a short pad of silica and the silica washed with 30% EtOAc/hexanes. The organic
layers are combined and evaporated to yield the epimerized trans diester in
60% yield as a inseparable mixture of isomers (8:2 trans:cis).
We thank FAPESP (Research Supporting Foundation of the State
of Sa˜o Paulo) and CNPq, for financial support and a Ph.D. fellowship.
We also thank Angelo H. L. Machado for performing the theoretical
calculation on compound 17 and Professor Richard Chamberlin
(University of California, Irvine) for providing us data about com-
pound 3a.
Supplementary data
1H NMR, 13C NMR, and IR spectra for all new compounds. Sup-
plementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.08.001.
20. Petasis, N.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
21. Hanessian, S.; Fu, J. Can. J. Chem. 2001, 79, 1812.
22. (a) Masuda, K.; Okutani, T.; Kaneko, T. Chem. Pharm. Bull. 1974, 22, 1490; (b)
Masuda, K.; Okutani, T. Chem. Pharm. Bull. 1974, 22, 1498.
References and notes
1. (a) Kanai, Y.; Smith, C. P.; Hediger, M. A. Trends Neurosci. 1993, 16, 365; (b)
Szatkowski, M.; Attwell, D. Trends Neurosci. 1994, 17, 359.
2. (a) Conn, P. J.; Patel, J. The Metabotropic Glutamate Receptors; Humana: Totowa/
New Jersey, NJ, 1994; pp 1–277; (b) Hollmann, M.; Heinemann, S. Annu. Rev.
Neurosci. 1994, 17, 31; (c) Nakanishi, S. Neuron 1994, 13, 1031; (d) Nicolletti, F.;
Bruno, V.; Copani, A.; Casabona, G.; Kno¨pfel, T. Trends Neurosci. 1996, 19, 267.
23. Marchand, A. P.; Bartnik, R. Synlett 1997, 1029.
24. Conditions employed different protocols for Jones oxidation and IBX oxidation
to the aldehyde, followed by Pinick oxidation.
25. Jiang, J.; Shah, H.; Devita, R. J. Org. Lett. 2003, 5, 4101.
26. Frank Lovering Ph.D. Thesis (www.umi.com/proquest), under the supervision
of Richard Chamberlin (University of California, Irvine).