Asymmetric synthesis of cis-2,4-disubstituted azetidin-3-ones from metal carbene chemistry

Article abstract of DOI:10.1016/j.jorganchem.2005.07.016

Several chiral cis-2,4-disubstituted azetidin-3-ones were prepared as single diastereoisomers from N-protected amino acids, employing a highly stereoselective copper carbenoid N-H insertion reaction of diazoketones. These azetidin-3-ones were then convert

Full text of DOI:10.1016/j.jorganchem.2005.07.016

Journal of Organometallic Chemistry 690 (2005) 5636–5646
www.elsevier.com/locate/jorganchem
Asymmetric synthesis of cis-2,4-disubstituted azetidin-3-ones
from metal carbene chemistry
*
Antonio Carlos B. Burtoloso, Carlos Roque D. Correia
Instituto de Quı´mica, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, CEP 13083-970, Campinas, SP, Brazil
Received 25 May 2005; accepted 4 July 2005
Available online 22 August 2005
Abstract
Several chiral cis-2,4-disubstituted azetidin-3-ones were prepared as single diastereoisomers from N-protected amino acids,
employing a highly stereoselective copper carbenoid N–H insertion reaction of diazoketones. These azetidin-3-ones were then con-
verted into fully substituted azetidines in a few steps in good to high yields.
Ó 2005 Elsevier B.V. All rights reserved.
Keywords: Metal carbenes; Azetidines; Azetidin-3-ones; N–H insertion; Diazoketones
1. Introduction
azetidine compounds, new protocols are not only neces-
sary but also highly desirable.
Among the many nitrogen heterocycles the azetidine
compounds are, most probably, the least investigated
ones. The literature reports a reasonable number of syn-
thetic methodologies and applications of azetidines, but
these figures are still small when compared to other cyc-
lic amines such as pyrrolidines and aziridines. Natural
azetidines are rather rare compounds and are found
mainly as sphingosine-like compounds, many of which
display interesting biological activities [1]. Regarding
the synthetic applications of chiral azetidines, the major-
ity of the examples reported have been concentrated in
the area of chiral ligands [2]. Studies related to the syn-
thesis of fully substituted azetidines are likewise scarce
in the literature and focused mainly in the synthesis of
natural azetidines [3]. Most of these studies centered
on the preparation of azetidines are based on an intra-
molecular nucleophilic substitution [4]. In view of the
scarcity of methodologies to construct fully-substituted
2. Discussion
In the last few years [5], we have been engaged in the
synthesis of chiral azetidin-3-ones [6] employing metal
carbene chemistry as the key synthetic step. In a recent
communication [5a], we have shown that the cis-2,4-
disubstituted azetidin-3-one 1 (Scheme 1), prepared by
a new copper catalyzed N–H insertion reaction of dia-
zoketones, could be easily converted to the chiral azeti-
dine 2, a short sphingosine analogue. These results
clearly show that azetidin-3-ones such as 1 are powerful
intermediates for the synthesis of fully substituted azeti-
dines in a few steps.
In this paper our aim is several fold: (a) we would like
to construct several cis-2,4-disubstituted azetidin-3-ones
from chiral diazoketones by means of a metal-catalyzed
N–H insertion reaction; (b) apply these azetidin-3-ones
in the synthesis of fully-substituted azetidines; (c) to
understand the stereochemical outcome of these metal-
catalyzed N–H insertion reactions; and (d) to evaluate
*
Corresponding author.
E-mail address: roque@iqm.unicamp.br (C.R.D. Correia).
0022-328X/$ - see front matter Ó 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2005.07.016

A.C.B. Burtoloso, C.R.D. Correia / Journal of Organometallic Chemistry 690 (2005) 5636–5646
5637
OH
O
O
Cu(acac)2
TBDPSO
TBDPSO
H
N
H
NP
N2
HO
N
P
3 steps
P= Boc or Ts
2
1
diazoketone
Scheme 1. Synthesis of a small chain sphingosine analogue.
the scope of the methodology with regard to the diaste-
reoselectivity of the N–H insertion reaction.
employing, a,a0-dialkyl-a-diazoketones as starting
materials.
The synthesis of cis-2,4-disubstituted azetidin-3-ones
have been previously reported by us [5a], De Kimpe
[7] and Kise [8]. The work of De Kimpe and Kise are
based on the alkylation of 2-substituted azetidin-3-ones
and on the electroreductive intramolecular coupling of
iminoesters, respectively.
Metal carbene chemistry has been widely used as an
efficient tool in organic chemistry [9]. Despite some
examples in the literature using rhodium and copper cat-
alysts in N–H insertion reactions of a-diazoketones to
form a four-membered ring (azetidin-3-ones), these ef-
forts have been mainly restricted to the preparation of
the structurally simpler 2-substituted azetidin-3-ones
[10] (Scheme 2). Therefore, our initial goal was to
extend the metal carbene chemistry to the preparation
of the more complex 2,4-disubstituted azetidin-3-ones,
To start with, we prepared the N-Boc and N-tosyl
diazoketones 3 and 4 (Scheme 3) for the N–H
insertion reactions. Surprisingly, while diazoketone 3
(N-Boc) could be prepared in 50–55% yield by addition
of diazobutane [11] to a mixed anhydride [10d,12], the
N-tosyl diazoketone 4 could not be prepared by the
same methodology. However, reaction of diazobutane
with the intermediate acyl chloride [10h,12], furnished
the N-tosyl diazoketone 4 in an overall yield of 41–
45%. The moderate yields obtained for these reactions
can be ascribed to the lower reactivity of higher dia-
zoalkanes when compared to diazomethane. The superi-
ority of diazomethane was clearly demonstrated when
we replaced diazobutane by diazomethane during prep-
aration of diazoketones 5 and 6 (Scheme 3).
Diazoketones 3 and 4 were then submitted to N–H
insertion reactions under several reaction conditions
aiming at finding the best experimental protocol to pre-
pare the 2,4-disubstituted azetidin-3-ones (Scheme 4).
The best conditions found for the synthesis of the
azetidin-3-ones were obtained when using copper acetyl-
acetonate or copper acetate and the N-tosyl diazoketone
4 in refluxing benzene (entries 10, 11 and 16, Table 1). It is
worth mentioning that in all cases where azetidin-3-ones
where isolated only the cis stereoisomer was detected.
The cis stereochemistry was assigned based on nOe
experiments and will be discussed in more details below.
Together with the cis-2,4-disubstituted-azetidin-3-ones,
O
O
R
catalyst
catalyst
R
O
N
P
H
NP
N2
R = alkyl
P = protecting group
O
O
O
OR
H
NP
N2
N
P
OR
Scheme 2. Insertion reactions for the synthesis of 2-substituted
azetidin-3-ones.
O
O
O
TBDPSO
PNH N2
O
a
TBDPSO
TBDPSO
OH
O
OEt
N2
3 (P=Boc), 50-55%
4 (P=Ts), 41-45%
HNBoc
N-Boc-O-TBDPS-L-serine
HNBoc
diazobutane
O
O
O
b
H
TBDPSO
TBDPSO
N2
TBDPSO
OH
Cl
PNH N2
HNTs
HNTs
N-Ts-O-TBDPS-L-serine
H2C
5 (P=Boc), 95-98%
6 (P=Ts), 81%
diazomethane
a: ClCOOEt, Et3N, THF, -21-0oC, 30 min. Then, diazoalkane, 0oC-rt, 2h. b: ClCOCOCl, CH2Cl2, 0oC-rt, 2h. Then, THF, diazoalkane, 0oC,
2h.
Scheme 3. Preparation of diazoketones via acyl chlorides and mixed anhydrides.

5638
A.C.B. Burtoloso, C.R.D. Correia / Journal of Organometallic Chemistry 690 (2005) 5636–5646
O
O
O
catalyst
+
TBDPSO
TBDPSO
reaction conditions
N
P
PNH
PNH N2
TBDPSO
9 (P=Boc)
10 (P=Ts)
3 (P=Boc)
4 (P=Ts)
7 (P=Boc)
8 (P=Ts)
diazoketone
olefin
azetidin-3-one
single stereoisomers (0-77%)
Scheme 4. Metal catalyzed N–H insertion in the synthesis of 2,4-disubstituted azetidin-3-ones.
Table 1
Conditions evaluated for the metal catalyzed N–H insertion
Entry
Diazoketone
Catalysta
Conditionsb
Azetidin-3-one (%)c
Olefin (%) (E:Zc)
9 (nd)d
1
2
3
4
5
6
7
8
9e
10
11g
12
13
14
15
16
17
18
3
3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
Rh2(OAc)4
Cu(acac)2
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(cap)4
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(OAc)2.H2O
CuCl2
CH2Cl2, 0 °C, 1 h
CH2Cl2, rt, 12 h
CH2Cl2, rt, 15 min
C6H6, rt, 45 min
C6H6, reflux, 1 min
CH2Cl2, rt, 12 h
CH2Cl2, rt, 24 h
C6H6, rt, 24 h
C6H6, 60 °C, 45 min
C6H6, reflux, 1 min
C6H6, reflux, 1 min
PhMe, reflux, 1 min
CH2Cl2, rt, 12 h
C6H6, rt, 12 h
7 (ꢀ 35)
Complex mixture
8 (0)
8 (0)
8 (0)
8 (0)
No reaction
8 (0)
10 (89) (10:90)
10 (63) (25:75)
10 (81) (33:67)
10 (77) (25:75)
10 (67) (100:0)
10 (35) (70:30)
10 (22) (66:34)
10 (18) (95:05)
10 (74) (65:35)
10 (80) (70:30)
10 (85) (51:49)
10 (90) (64:36)
10 (17) (67:33)
10 (60) (82:18)
10 (55) (69:31)
8 (41)
8 (67) (61)f
8 (62)
8 (traces)
8 (0)
8 (0)
8 (0)
8 (77)
C6H6, reflux, 1 min
C6H6, reflux, 1 min
C6H6, reflux, 1 min
C6H6, reflux, 1 min
8 (36)
8 (21)
CuBr.SMe2
Abbreviations. Cu(acac)2: bis(acetylacetonato)copper(II); Cu(hfacac)2: bis(trifluoracetylacetonato)copper(II); Rh2(cap)4: dirhodium(II) capro-
lactamate.
a
Rh2(OAc)4: 2 mol%, Cu catalysts: 10 mol%.
Catalyst was added in one portion after the desired temperature was attained (except for entry 11g). All the reactions were performed in a 0.05 M
b
solution of the diazo compound.
c
Azetidin-3-one 8 and the olefins have similar Rf and their ratios were determined by 1H RMN analysis after filtration of the crude mixture on
silica (30% EtOAc/hexane). To assure the validity of the 1H RMN analysis, the ratio of the compounds obtained in entry 10 was also determined
after separation by flash chromatographyf (10% EtOAc/hexane).
d
E:Z ratio not determined. The reaction furnished an inseparable mixture of products.
Internal temperature.
Isolated yields (flash chromatography).
Addition of the catalyst as a solution in CH2Cl2.
e
f
g
two side products were isolated and characterized as the
olefins 10a (E) and 10b (Z). Interestingly, the ratio be-
tween these two olefins varies greatly according to the
reaction conditions, mainly with respect to the catalyst
employed. For example, reaction conditions described
in entry 8 (Cu(acac)2 as catalyst) furnished exclusive the
E olefin 10a, whereas conditions described in entry 3
(Rh2(OAc)4 as catalyst) provided the Z olefin 10b as
the major stereoisomer. A clear trend was observed from
these studies: the Z olefins predominate under Rh catal-
ysis while copper catalysis favors the E olefins. This rela-
tionship between the E:Z olefin ratio and the metal
catalyst employed can be ascribed to the size of these me-
tal catalysts. Fig. 1 illustrates the two possible pathways
for the b-hydride elimination leading to the E and Z ole-
fins. In the Newman projection leading to the E olefin
(representation A) the alkyl group attached to C2 is
placed next to (synperiplanar) the metal catalyst, whereas
in the Newman projection leading to the Z olefin (repre-
sentation B) the alkyl group is farther apart from the me-
tal and closer to the OTBDPS group. The active catalyst
species for the copper(II) catalysts should be a Cu (I)
bearing one ligand [9,13] and comparing its size to that
of Rh2(OAc)4 and Rh2(cap)4, the Rh catalyst is the bulk-
iest catalyst. We believe that under Rh catalysis, path B
should be the preferred one leading to the Z olefins
whereas under copper catalysis path A is the main route,
therefore leading to the E olefins.

A.C.B. Burtoloso, C.R.D. Correia / Journal of Organometallic Chemistry 690 (2005) 5636–5646
5639
O
TBDPSO
O
O
olefin E
Rh or Cu
catalysts
TsNH
+
C2
C1
β-hydride elimination
TBDPSO
TBDPSO
TsNH MLx
O
TsNH N2
carbenoid
TBDPSO
diazoketone
TsNH
olefin Z
HNTs
HNTs
TBDPSO
O
TBDPSO
O
R
H
R
olefin Z
H
olefin E
C
H
C
1
1
H
MLx
Path B (Rh catalyst)
MLx
Path A (Cu catalysts)
Fig. 1. Rationale for the b-hydride elimination.
Noteworthy, the above protocol for preparing azeti-
din-3-ones from N-tosyl amino acids does not promote
epimerization of the incipient center at C2. Chiral
HPLC analyses confirmed the stereochemical integrity
of theses azetidin-3-ones [14]. Having established the
best conditions for carrying out the synthesis of the dia-
zoketones and their conversion into the corresponding
azetidin-3-ones we decided to prepare a number of azeti-
din-3-ones in order to probe the scope of the methodol-
ogy. In all the cases examined, the cis-azetidin-3-ones
14–16 were synthesized in moderate yields as the only
observable stereoisomer [15] (Scheme 5).
The cis stereochemical outcome observed for the
N–H insertion reaction was supported by nOe experi-
ments on azetidin-3-ones 8, 14, 15, 16 (Fig. 2). For azeti-
din-3-ones 8 and 15 the hydrogens at C2 and C4
O
Cu(acac) ,
10 mol%
2
1) oxalyl chloride,
O
O
CH Cl
2
2
R'
R
R'
R'
R
OH
N
C H , reflux,
2) THF, RCHN
6
6
2
TsNH
N
2
TsNH
1 min
Ts
O
O
TBDPSO
TBDPSO
N
TBDPSO
8 61%
TsNH
N
2
[α] + 25 (c 1.13, CHCl )
Ts
D
3
4 41-50%
O
O
OCH
3
OCH
3
N
TBDPSO
14 65%
TsNH
N
2
[α] +30 (c 1.70, CHCl )
Ts
D
3
40%
11
O
O
TBDPSO
N
TBDPSO
TsNH
N
2
[α] +31 (c 1.43, CHCl )
Ts
D
3
15 71%
12 55%
O
O
N
HNTs N
2
[α] + 136 (c 0.46, CHCl )
Ts
D
3
13 32%
16
47%
Scheme 5. Synthesis of azetidin-3-ones from diazoketones.

5640
A.C.B. Burtoloso, C.R.D. Correia / Journal of Organometallic Chemistry 690 (2005) 5636–5646
anism is still unclear, but a stepwise mechanism involv-
3%
HO
3%
ing ylides [9] as well as concerted three or four-centered
TS have been proposed [17]. As depicted in Fig. 3, both
the concerted three-centered and the ylide process can
explain the observed stereochemical outcome. There-
fore, a plausible explanation for the interesting cis ste-
reochemical outcome can be put forward considering a
transition state where both the alkyl group and the
bulky MLn (Rh2(OAc)4 or Cu(acac)2) are anti.
H
3
nOe = 0.6-0.8%
O
H
H
4
2
O
R
R'
H
N
2
H
4
NaBH4
H
2
H
4
Ts
+
R
R'
N
R
R'
1%
HO
N
1%
Ts
8 and 15
Ts
H
3
14 and 16
H
H
4
2
To further demonstrate the synthetic potential of the
azetidin-3-ones synthesized in this work, we have con-
structed the fully-substituted azetidine 19 starting from
N-Boc-azetidin-3-one 7 or N-tosyl-azetidin-3-one 8
(Scheme 7). Introduction of the alcohol functionality
at C3 was carried out by reducing azetidin-3-one 7 with
NaBH4 at ꢁ21 °C in CH3OH. The only detectable dia-
stereoisomer, the all cis azetidin-3-ol 17 (Re face attack
of the hydride at C3), was already expected as the major
diastereoisomer, since the Si face of the carbonyl in aze-
tidinone 7 was rather congested by the C2 and C4
groups. Previous results from our laboratory and some
precedents from the literature [10d] confirm this stereo-
chemical trend. Cleavage of the TBDPS group of 17
with tetrabutylammonium fluoride (TBAF) followed
by treatment of the free diol 18 with trifluoroacetic acid
furnished the azetidine alkaloid analogue 19 in 71%
(over two steps). Starting with N-tosyl-azetidin-3-one 8
we carried out the synthesis in a very similar manner.
Reduction of 8 with NaBH4 at ꢁ21 °C in CH3OH gave
a separable mixture of the cis (50%) and trans (20%)
azetidin-3-ols 20a and 20b. After chromatographic sepa-
ration, cleavage of the tosyl group of 20a with Na/naph-
thalene in DME, followed by treatment of the crude
amine 21 with tetrabutylammonium fluoride (TBAF)
provided (after acidification with trifluoroacetic acid)
the azetidine salt 19 in 50% yield (over two steps)
(Scheme 7).
R
R'
N
Ts
Fig. 2. nOe studies on azetidin-3-ones.
displayed similar chemical shifts and no nOe experi-
ments could be realized. However, nOe experiments car-
ried out on the corresponding alcohols of azetidinones 8
and 15 permitted unambiguous assignments.
The influence of the catalyst loading in the N–H
insertion reactions was also investigated (Scheme 6).
Varying the catalyst loading from 100 to 5 mol% did
not affect the yield of the carbenoid N–H insertion prod-
uct significantly. However, catalyst loading below
1 mol% caused a drastic decrease in yields.
Despite intense investigations on the mechanism of
C–H insertion by rhodium carbenoids [16] the N–H
insertions have not been investigated to the same extent
and the analogy between these two processes is not
straightforward. Nakamura [16c] and co-workers have
reported an interesting theoretical study for C–H inser-
tion assuming a concerted but nonsynchronous (three-
centered hydride transfer) transition state, whereas a
synchronous three-centered concerted transition state
was proposed by Doyle et al. [16b]. The N–H insertion
deserves a different approach because of the nonbonding
electron pair on the nitrogen. The N–H insertion mech-
O
O
OCH
3
OCH
3
TBDPSO
Cu(acac)
2
N
Ts
TBDPSO
TsNH
N
2
C H , reflux,
11
14
6
6
single stereoisomer
1 min
entry Cu(acac)2 (mol %)a azetidin-3-oneb (%)
1
2
3
4
5
100
10
5
63
64
64
1
55
0.1
no reaction
a.The catalyst was added as a solution in 0.65 mL of CH2Cl2. All the reactions were performed with 0.06 mmol of the diazo
compound in 1.2 mL of C6H6; b. Isolated yield.
Scheme 6. Catalyst loading studies.

A.C.B. Burtoloso, C.R.D. Correia / Journal of Organometallic Chemistry 690 (2005) 5636–5646
5641
O
O
catalyst
R1
R2
R1
R2
HNP
N
P
N2
three-centered concerted mechanism
ylide mechanism
δ
L M
n
R1
R1
R1
R2
R2
H
H
H
P
P
P
δ
N
H
δ
δ
δ
N
N
O
O
O
H
R2
H
L M
n
MLn
δ
unfavorable transition state
(highly hindered)
Favorable transition state
Favorable transition state
O
O
O
R1
R2
cis
R1
R2
cis
R1
R2
trans
N
P
N
P
N
P
Fig. 3. Rationale for the cis stereochemistry.
OH
OH
O
N
OH
b
c
a
CF3COO
N
N
H
N
HO
HO
TBDPSO
TBDPSO
18
17
H
Boc
Boc
Boc
19
N-Boc-azetidin-3-one 7
f
OH
OH
OH
O
e
d
+
TBDPSO
N
N
H
N
N
TBDPSO
TBDPSO
21
TBDPSO
Ts 20a
Ts 20b
Ts
N-Ts-azetidin-3-one 8
a: NaBH4, MeOH, -21oC, 30 min (46%). b: TBAF, THF, 0oC-rt, 3h (71%). c: TFA, CH2Cl2, 0oC, 1h (quantitative). d: NaBH4, MeOH,
-21oC, 30 min (50% cis and 20% trans). e: Na/naphthalene/DME. f: TBAF, THF, 0oC-rt, 3h then, TFA (50%).
Scheme 7. Synthesis of the sphingosine analogue 19.
The cis stereochemistry was confirmed by nOe exper-
iments on azetidin-3-ols 17, 18 and 20 (Fig. 4). Irradia-
tion at H3 of alcohol 17 showed a nOe with H2 and H4
of 3.0% for each hydrogen, while irradiation of the CH2
at C4, showed a nOe with the secondary hydroxyl of
1.8%. For azetidinol 18, a nOe was observed involving
H2 (1.5%) and H4 (1.4%) when H3 was irradiated, as
well as a small nOe (0.5%) involving the hydroxyl group
when the methylene of the CH2OH group was
irradiated.
In the case of azetidin-3-ols 20a and 20b identical nOe
values were observed for H2 and H4 when H3 was irra-
diated and are strong evidence for the cis stereochemis-
try of the alkyl groups at C2 and C4. The correct
stereochemistry for compounds 20a (cis, cis) and 20b
(trans, trans) were also suggested by the magnitude of
the nOe values (3.0% and 1.0%, respectively).
3. Conclusion
In summary, we have demonstrated that metal carbe-
noid insertion of a,a0-dialkyl-a-diazoketones can be a
viable and effective tool for the construction of fully
substituted azetidines from commercially available ami-
no acids. Chiral cis-2,4-disubstituted azetidin-3-ones
were readily prepared in just two steps from the protected
amino acids by the addition of diazoalkanes followed by
a metal catalyzed N–H insertion of the diazoketone
formed. The combination of N-tosyl diazoketones with

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A.C.B. Burtoloso, C.R.D. Correia / Journal of Organometallic Chemistry 690 (2005) 5636–5646
3.0%
3.0%
3.0%
3.0%
H4
H
1.8%
O
N
HO H3
HO H3
H4
H
H2
H2
H
TBDPSO
TBDPSO
TBDPSO
N
N
17 Boc
17
Boc
20a
Ts
1.0%
1.0%
1.4%
H4
1.5%
H
O
0.5%
H
HO H3
N
H
H
H4
HO H3
N
H2
H
H2
TBDPSO
N
HO
HO
20b
Boc
18
Ts
18
Boc
Fig. 4. nOe studies on the synthesized azetidines.
the cheap Cu(acac)2 or Cu(OAc)2 catalysts provided the
highest yields for the N–H insertion reactions. The meth-
odology can also be applied to the synthesis of several cis-
2,4-disubstituted azetidin-3-ones, depending only on the
amino acid and diazoalkane employed.
4.2.1. (S)-N-(tert-butyloxycarbonyl)-O-(tert-
butyldiphenylsilyl)-serine
Quantitative yield following the procedure above.
White solid, m.p. 147–149 °C. 1H NMR (300 MHz,
CDCl3): d = 7.56–7.69 (m, 4H), 7.32–7.48 (m, 6H),
5.40 (d, J = 8.8 Hz, 1H), 4.44 (m, 1H), 4.12 (dd,
J = 10.3, 2.2 Hz, 1H), 3.91(dd, J = 10.3, 2.9 Hz, 1H),
1.45 (s, 9H), 1.04 (s, 9H). 13C NMR (75 MHz, CDCl3):
d = 175.4, 155.3, 135.4, 135.3, 132.7, 132.4, 129.8, 127.7,
80.2, 64.3, 55.4, 28.4, 26.8, 19.4. IR (cmꢁ1): 3448, 3277,
3077, 3052, 2964, 2935, 2862, 1724, 1665, 1176, 1113,
703. ESI-MS: 444 (M + 1), 310, 266, 238, 232, 188,
160. HRMS m/z Calc. for C20H24NO4Si (M+ ꢁ OtBu)
370.1475, Found: 370.1367.
4. Experimental
4.1. General procedures
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, DMF and CH2Cl2 were distilled
from calcium hydride and THF were distilled from
Na. Rh2(OAc)4 [18] and Cu(acac)2 [19] were prepared
4.2.2. (S)-N-(p-toluene-sulphonyl)-O-(tert-
butyldiphenylsilyl)-serine
1
as described in the literature. H NMR and 13C NMR
70–90% yield after column chromatography, 5%
MeOH/chloroform as eluent. Colorless amorphous so-
data were recorded on a Varian Gemini 2000 (7.0 T)
or Varian Inova (11.7 T) spectrometer. High resolution
mass spectra (HRMS) were measured on a VG Auto-
spec-Micromass spectrometer. IR spectra were obtained
on a Thermo-Nicolet IR-200 spectrometer. Optical rota-
tions were measured at 25 °C with a Perkin–Elmer 241
instrument.
1
lid. H NMR (300 MHz, CDCl3): d = 7.18–7.72 (14H,
Ar), 5.53 (d, J = 8.1 Hz, 1H), 3.95–4.08 (m, 2H), 3.78
(dd, J = 9.5, 3.7 Hz, 1H), 2.36 (s, 3H), 0.95 (s, 9H).
13C NMR (75 MHz, CDCl3): d = 174.1, 143.6, 136.7,
135.3, 132.1, 132.0, 129.9, 129.5, 127.7, 126.9, 64.8,
57.1, 26.8, 21.6, 19.3. IR (cmꢁ1): 3277, 2929, 2856,
1727, 1427, 1427, 1334, 1163, 1112. HRMS m/z Calc.
for C22H22NO5SSi (M+ ꢁ tBu) 440.0988, Found:
440.1084.
4.2. General procedure for the protection of N-Boc-L-
serine [20] and N-Ts-L-serine [21] with TBDPSCl
To
a
4.0 M solution of N-protected serine
4.3. General procedure for the preparation of
diazoketones
(43.0 mmol) in dry DMF was added 150.5 mmol of
imidazole and 53.8 mmol of TBDPSCl. The viscous
mixture was stirred for 36 h and then the solvent evapo-
rated in vacuum. Next, water was added to the crude
product followed by addition of a 10% solution of citric
acid (pH 3.0) under stirring. The product was extracted
with Et2O (3x). NaCl was added to the aqueous layer
and extracted once again with Et2O. The combined or-
ganic layers were dried over anhydrous Na2SO4, evapo-
rated in vacuum and the residue subjected to column
chromatography when necessary.
4.3.1. Procedure A (via mixed anhydride)
To a solution of the N-Boc amino acid (3.41 mmol) in
17 ml of dry THF was added 3.75 mmol of dry Et3N.
The solution was then cooled to ꢁ21 °C and 3.75 mmol
of ethyl chloroformate was added dropwise. The reac-
tion flask was then allowed to warm to 0 °C. After stir-
ring for 30 min at 0 °C, a solution of freshly prepared
diazoalkane in ether was added (excess) and the stirring
continued for 2 h at room temperature. After this time

A.C.B. Burtoloso, C.R.D. Correia / Journal of Organometallic Chemistry 690 (2005) 5636–5646
5643
the solution was concentrated in vacuum and the crude
product purified by flash column chromatography.
2855, 2081, 1616, 1164, 1111, 1091, 702. HRMS m/z Calc.
for C28H33N3O4SSi 535.1961, Found: 535.1982.
4.3.2. (2S)-2-(N-tert-butyloxycarbonyl)-amino-1-tert-
butyldiphenylsilyloxy-4-diazo-heptan-3-one (3)
4.4.3. (2S)-2-(N-p-toluene-sulphonyl)-amino-1-tert-
butyldiphenylsilyloxy-4-diazo-6-methoxy-hexan-3-one
(11)
Purified by flash column chromatography (3% ethyl
acetate/chloroform) (35–40% yield), pale yellow oil. H
NMR (300 MHz, CDCl3): d = 7.20–7.78 (m, 14H),
5.48 (d, J = 8.8 Hz, 1H), 4.26 (ddd, J = 9.2, 8.8,
4.9 Hz, 1H), 3.74 (dd, J = 9.2, 4.9 Hz, 1H), 3.60 (br t,
J = 9.2 Hz, 1H), 3.29 (m, 2H), 3.22 (s, 3H), 2.41 (s,
3H), 2.39 (m, 2H), 0.99 (s, 9H). 13C NMR (75 Hz,
CDCl3): d = 189.5, 143.6, 135.4, 132.2, 130.0, 129.9,
129.5, 127.8, 127.7, 127.1, 70.3, 67.7, 65.4, 58.7, 57.2,
26.7, 23.5, 21.6, 19.1. IR (cmꢁ1): 3233, 3069, 2930,
2858, 2088, 1616, 1351, 1164, 1112, 1091, 733, 702.
HRMS m/z Calc. for C26H28NO5SSi (M+ ꢁ N2,-tBu)
494.1457, Found: 494.1490.
Purified by flash column chromatography (10% ethyl
acetate/hexane with 1% of Et3N), yellowish oil (50%).
1H NMR (300 MHz, C6D6, 70 °C): d = 7.64–7.80 (m,
4H), 7.19–7.28 (m, 6H), 5.34 (m, 1H, NH), 4.84 (m,
1H, CH), 3.86 (d, J = 6.1 Hz, 2H), 2.02–2.12 (m, 2H),
1.00–1.52 (2s-18H, 1m-2H), 0.70 (t, J = 7.3 Hz, 3H).
IR (cmꢁ1): 3350, 3072, 3052, 2964, 2930, 2867, 2085,
1714, 1636, 1113, 707. ESI-MS: 510 (M + 1), 342, 304,
287, 226, 220. HRMS m/z Calc. for C24H31NO4Si
(M+ ꢁ N2, -isobutene) 425.2022, Found: 425.2086.
1
4.4. Procedure B (via acyl chloride)
To a solution of the N-tosyl amino acid (1.13 mmol)
in 6.0 ml of dry CH2Cl2 at 0 °C was added 1.36 mmol of
oxalyl chloride (1.2 equiv.), followed by one drop of dry
DMF. After 2 h of stirring at room temperature, the sol-
vent was evaporated in vacuum and 6.0 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 solution was concentrated in
vacuum and the crude product purified by flash column
chromatography.
4.4.4. (1S)-1-(N-p-toluene-sulphonyl)-amino-3-diazo-1-
phenyl-butan-2-one (13)
In this case, 1.5 equiv. of oxalyl chloride were used in-
stead of 1.2. Purified by flash column chromatography
(30% ethyl acetate/hexane containing 1% of Et3N)
(32% yield), pale yellow oil. 1H NMR (300 MHz,
CDCl3): d = 7.49 (d, J = 8.1 Hz, 2H), 7.04–7.30 (m,
7H), 6.16 (broad d, 1H), 5.21 (d, J = 6.6 Hz, 1H), 2.35
(s, 3H), 1.83 (s, 3H). 13C NMR (75 MHz, CDCl3):
d = 188.0, 143.0, 137.3, 129.1, 128.5, 127.8, 126.8, 62.9,
61.0, 21.5, 8.3. IR (cmꢁ1): 3358, 3257, 3060, 2929,
2083, 1611, 1351, 1165. HRMS m/z Calc. for
C17H17N3O3S 343.0991, Found: 343.0992.
4.4.1. (2S)-2-(N-p-toluene-sulphonyl)-amino-1-tert-
butyldiphenylsilyloxy-4-diazo-heptan-3-one (4)
Purified by flash column chromatography (20% ethyl
acetate/hexane with 1% of Et3N), pale yellow oil
(41–45% yield). 1H NMR (500 MHz, CDCl3): d =
7.24–7.72 (14H, Ar), 5.55 (d, J = 8.9 Hz, 1H, NH),
4.20–4.30 (m, 1H, CH), 3.77 (dd, J = 5.2, 9.8 Hz, 1H),
3.62 (m, 1H), 2.41 (s, 3H), 2.04–2.17 (m, 2H), 1.29 (m,
2H), 1.01 (s, 9H), 0.84 (t, J = 7.3 Hz, 3H). 13C NMR
(125 MHz, CDCl3): d = 189.8, 143.7, 136.8, 135.4,
132.2 (2s), 129.9 (2s), 129.6, 127.8 (2s), 127.0, 68.5,
65.4, 57.2, 26.6, 24.5, 21.4, 20.2, 19.0, 13.2. IR (cmꢁ1):
3253, 2959, 2930, 2859, 2078, 1616, 1164, 1112, 1091,
702. HRMS m/z Calc. for C26H28NO4SSi (M+ ꢁ N2,-
tBu) 478.1508, Found: 478.1587.
4.5. General procedure for the preparation of N-tosyl
azetidin-3-ones
0.63 mmol of diazoketone was dissolved in 13 ml of
benzene and the yellow solution heated to reflux. Next,
10 mol% of Cu(acac)2 was added in portions to the reac-
tion turning the reaction mixture from yellow to brown
immediately, with vigorous liberation of nitrogen. CAU-
TION: liberation of nitrogen can be quite violent and
large scale reactions (more than 10 mmols) should be car-
ried out in a large reaction flask to permit nitrogen liber-
ation (open system). After one minute, the reaction was
cooled, the solvent evaporated, and the crude product
purified by flash column chromatography to furnish
the corresponding azetidin-3-one.
4.4.2. (2S)-2-(N-p-toluene-sulphonyl)-amino-1-tert-
butyldiphenylsilyloxy-4-diazo-pentan-3-one (12)
Purified by flash column chromatography (20% ethyl
acetate/hexane containing 1% of Et3N) (55% yield), pale
1
yellow oil. H NMR (300 MHz, CDCl3): d = 7.20–7.72
4.5.1. (2S 4R)-N-(p-toluene-sulphonyl)-2-(tert-
(m, 14H), 5.46 (d, J = 8.8 Hz, 1H), 4.24 (m, 1H), 3.74
(m, 1H), 3.58 (m, 1H), 2.41 (s, 3H), 1.75 (s,3H), 0.99 (s,
9H). 13C NMR (75 MHz, C6D6): d = 190.0, 142.9,
138.4, 135.8, 135.2, 130.2, 129.5, 128.1, 127.4, 65.6, 57.4,
27.0, 21.2, 19.4, 8.1. IR (cmꢁ1): 3227, 3072, 3043, 2927,
butyldiphenylsilyloxymethyl)-4-propyl-azetidin-3-one (8)
Purified by flash column chromatography (10% ethyl
acetate/hexane) (61% yield), colorless oil. 1H NMR
(300 MHz, CDCl3): d = 7.28–7.80 (14H, Ar), 4.67 (t,
J = 2.5 Hz, 1H, H2), 4.62 (t, J = 7.3 Hz, 1H, H4),

5644
A.C.B. Burtoloso, C.R.D. Correia / Journal of Organometallic Chemistry 690 (2005) 5636–5646
3.78–3.90 (2dd, J = 11.7, 2.9 Hz, 2H), 2.44 (s, 3H), 1.92
(q, J = 7.3 Hz, 2H), 1.51 (m, 2H), 1.04 (s, 9H), 0.90 (t,
J = 7.3, 3H). 13C NMR (75 MHz, CDCl3): d = 198.4,
144.4, 135.4, 132.4 (2s), 129.6 (2s), 128.1, 127.6, 83.2,
83.6, 61.6, 32.2, 26.6, 21.6, 19.2, 18.4, 13.8. IR (cmꢁ1):
3075, 2962, 2931, 2856, 1826, 1429, 1350, 1165, 1109,
825, 705. HRMS m/z Calc. for C26H28NO4SSi
(M+ ꢁ tBu) 478.1508, Found: 478. 1328.
(300 MHz, CDCl3): d = 7.30–7.84 (14H, Ar), 4.74 (dd,
J = 7.3, 5.9 Hz, 1H), 4.63 (t, J = 2.9 Hz, 1H), 3.92 (dd,
J = 11.7, 2.9 Hz, 1H), 3.87 (dd, J = 11.7, 2.9 Hz, 1H),
3.48–3.67 (m, 2H), 3.31 (s, 3H), 2.44 (s, 3H), 2.02–2.28
(m, 2H), 1.04 (s, 9H). 13C NMR (75 MHz, CDCl3):
d = 198.1, 144.6, 135.5, 132.4, 131.6, 129.8, 129.7,
128.4, 127.6, 84.2, 80.3, 67.3, 61.9, 58.4, 30.1, 26.7,
21.7, 19.4. IR (cmꢁ1): 3076, 2924, 2856, 1822, 1354,
1165, 1103, 747, 704. HRMS m/z Calc. for
C26H28NO5SSi (M+-tBu) 494.1457, Found: 494.1291.
4.5.2. (2S) (4E)-2-(N-p-toluene-sulphonyl)-amino-1-
tert-butyldiphenylsilyloxy-hept-4-en-3-one (10a) (14%)
1H NMR (300 MHz, CDCl3): d = 7.16–7.74 (14H),
6.85 (dt, J = 16.1, 6.2 Hz, 1H), 6.11 (dt, J = 16.1,
1.5 Hz, 1H), 5.76 (d, J = 7.3 Hz, 1H), 4.19 (m, 1H),
3.91 (dd, J = 11.0, 3.7 Hz, 1H), 3.79 (dd, J = 11.0,
4.8 Hz, 1H), 2.37 (s, 3H), 2.16 (dq, 7.3, 1.5 Hz, 2H),
1.00 (t, J = 7.3 Hz, 3H), 0.97 (s, 9H). 13C NMR
(75 MHz, CDCl3): d = 194.4, 151.0, 143.1, 136.9,
132.5, 129.7, 129.4, 127.6, 126.9, 125.2, 64.9, 61.1,
26.8, 25.8, 21.6, 19.3, 12.0. IR (cmꢁ1): 3276, 3072,
3039, 2959, 2931, 2857, 1699, 1627, 1427, 1340, 1164,
1112, 1091, 702. HRMS m/z Calc. for C30H37NO4SSi
535.2213, Found: 535.2026.
4.5.6. (2S 4R)-N-(p-toluene-sulphonyl)-2-(tert-butyldip-
henylsilyloxymethyl)-4-phenyl-azetidin-3-one (16)
Purified by flash column chromatography (20% ethyl
acetate/hexane) (47% yield), colorless oil. 1H NMR
(300 MHz, CDCl3): d = 7.78 (d, J = 8.1 Hz, 2H), 7.30–
7.38 (m, 7H), 5.56 (s, 1H), 4.88 (q, J = 7.3 Hz, 1H),
2.45 (s, 3H), 1.51 (d, J = 7.3Hz, 3H).13C NMR
(75 MHz, CDCl3): d = 197.0, 144.8, 132.4, 132.2,
129.8, 128.7, 128.6, 128.3, 126.3, 84.2, 78.6, 21.7, 16.0.
IR (cmꢁ1): 3067, 3030, 2931, 2856, 1814, 1346, 1161,
1116, 1093. HRMS m/z Calc. for C17H17NO3S
315.0929, Found: 315.0937.
4.5.3. (2S) (4Z)-2-(N-p-toluene-sulphonyl)-amino-1-
tert-butyldiphenylsilyloxy-hept-4-en-3-one (10b) (8%)
1H NMR (300 MHz, CDCl3): d = 7.16–7.76 (15H),
6.04–6.20 (m, 1H), 5.77 (d, J = 7.3 Hz, 1H), 3.74–4.04
(2m, 3H), 2.50 (q, J = 7.3 Hz, 2H), 2.38 (s, 3H), 0.95–
1.05 (12H). 13C NMR (75 MHz, CDCl3): d = 194.8,
153.6, 143.2, 135.4, 129.7, 129.5, 127.8, 127.7, 127.6,
127.0, 126.9, 122.6, 64.7, 63.1, 26.8, 23.5, 21.6, 19.3,
13.4. IR (cmꢁ1): 3290, 3075, 3048, 2962, 2935, 2863,
1701, 1622, 1426, 1343, 1165, 1113, 1090, 705. ESI-
MS: 536 (M + 1), 458, 380, 350.
4.5.7. (2S, 4R)-N-(tert-butyloxycarbonyl)-2-(tert-
butyldiphenylsilyloxymethyl)-4-propyl-azetidin-3-one (7)
609 mg (1.2 mmol) of diazoketone 3 in 24 ml of dry
CH2Cl2 was cooled to 0 °C and 11 mg of Rh2(OAc)4
(2 mol%) were added. After 1 h, the solvent was re-
moved under vacuum and the crude product purified
by flash chromatography (5% ethyl acetate/hexane) to
give 223 mg of a mixture of two compounds displaying
almost identical Rfs. Reduction of this mixture with
NaBH4 in MeOH provided, after flash chromatography,
the azetidine-3-ol 17 and the unidentified side product
(33 mg). An analytical sample of azetidin-3-one 7 was
obtained by oxidation of the azetidin-3-ol 17 with IBX
in ethyl acetate under reflux. 1H NMR (300 MHz,
C6D6, 70 °C): d = 7.72–7.83 (m, 4H), 7.18–7.34 (m,
6H), 4.53 (t, J = 7.3 Hz, 1H, H4), 4.48 (t, J = 2.9 Hz,
1H, H2), 3.98 (dd, J = 11.7, 2.9 Hz, 1H), 3.81 (dd,
J = 11.7, 2.9 Hz, 1H), 2.02 (m, 1H), 1.88 (m, 1H),
1.04–1.64 (2s-18H, m-2H), 0.85 (t, J = 7.3, 3H). 13C
NMR (125 MHz, C6D6): d = 201.4, 156.5, 135.9,
133.3, 133.1, 130.0, 129.9, 128.1, 82.4, 81.4, 79.7, 61.8,
32.3, 28.2, 26.8, 19.3, 19.1, 13.9. IR (cmꢁ1): 3077,
3047, 2969, 2935, 2857, 1826, 1714, 1377, 1113, 712.
ESI-MS: 482 (M + 1), 348, 304, 226, 186. HRMS m/z
Calc. for C28H39NO4Si 481.2648, Found: 481.2461.
4.5.4. (2S 4R)-N-(p-toluene-sulphonyl)-2-(tert-butyldip-
henylsilyloxymethyl)-4-methyl-azetidin-3-one (15)
Purified by flash column chromatography (10% ethyl
acetate/hexane) (71% yield), colorless oil. 1H NMR
(300 MHz, CDCl3): d = 7.76 (d, J = 8.1 Hz, 2H), 7.62–
7.72 (m, 5H), 7.30–7.50 (m, 7H), 4.68–4.76 (m, 2H),
3.86 (dd, J = 12.5, 2.2 Hz, 1H), 3.81 (dd, J = 12.5,
2.2 Hz, 1H), 2.45 (s, 3H), 1.50 (d, J = 7.3 Hz, 3H),
1.03 (s, 9H). 13C NMR (75 MHz, CDCl3): d = 198.4,
144.4, 135.4, 132.7, 132.4, 129.8, 129.7, 128.2, 127.6,
83.6, 79.1, 61.4, 26.6, 21.7, 19.2, 15.0. IR (cmꢁ1): 3071,
3048, 2958, 2933, 2856, 1822, 1346, 1161, 1116, 956,
708. HRMS m/z Calc. for C28H33NO4SSi 507.1900,
Found: 507.1818.
4.6. Typical procedure for the reduction of azetidin-3-ones
4.5.5. (2S 4R)-N-(p-toluene-sulphonyl)-2-(tert-
butyldiphenylsilyloxymethyl)-4-(methoxy-etane)-
azetidin-3-one (14)
Purified by flash column chromatography (20% ethyl
acetate/hexane) (65% yield), colorless oil. 1H NMR
4.6.1. (2S, 3S, 4R)-N-(tert-butyloxycarbonyl)-2-(tert-
butyldiphenylsilyloxymethyl)-4-propyl-azetidin-3-ol (17)
102.9 mg (0.21 mmol) of azetidin-3-one 7 was dis-
solved in 1.0 ml of methanol and the solution was cooled

A.C.B. Burtoloso, C.R.D. Correia / Journal of Organometallic Chemistry 690 (2005) 5636–5646
5645
to ꢁ21 °C, followed by the addition of 20 mg of NaBH4.
After stirring for 30 min, a 1 M solution of NaHSO4 was
added (pH 3.0) and the methanol removed in vacuum.
The product was extracted four times with CH2Cl2
and the combined organic layers dried (Na2SO4) and
concentrated. After purification by flash column chro-
matography (20% ethyl acetate/hexane), alcohol 17
(47.5 mg) was obtained as a colorless oil in 46% yield.
1H NMR (300 MHz, CDCl3): d = 7.58–7.82 (m, 4H),
7.31–7.54 (m, 6H), 4.68 (dt, J = 10.3, 7.3 Hz, 1H, H3)
(turns into a triplet, J = 7,3 Hz, upon addition of
D2O), 4.34 (d, J = 10.3 Hz, 1H, OH), 4.14–4.30 (m,
2H, H2 and H4), 4,07 (m, 1H), 3.91 (dd, J = 11.7,
2.2 Hz, 1H), 1.74–2.00 (m, 2H), 1.26–1.56 (m, 2H),
1.01–1.20 (s, 9H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR
(75 MHz, CDCl3): d = 156.7, 135.3, 135.2, 132.0,
131.7, 129.7, 129.6, 127.6, 127.5, 79.2, 67.3, 66.6 (br),
64.9 (br), 63.4, 30.8, 28.3, 26.8, 19.2, 19.0, 14.2. IR
(cmꢁ1): 3487, 3082, 2969, 2930, 2857, 1699, 1367,
1123, 707. ESI-MS: 484 (M + 1), 384, 350, 306, 272,
228, 220. HRMS m/z Calc. for C28H41NO4Si 483.2805,
Found: 483.2695.
azetidin-3-ol 17 in 1.1 ml of THF at 0 °C. The solution
was stirred for 3 h followed by evaporation of the sol-
vent and purification of the crude product by flash col-
umn chromatography (60% ethyl acetate/hexane). Diol
18 was obtained as a white solid in 71% yield (5.6 mg).
1H NMR (300 MHz, CDCl3): d = 4.62 (q, J = 7.3 Hz,
1H, H3), 4.30 (m, 1H, H2), 4.21 (q, J = 7.3, 1H, H4),
3.99 (m, 1H), 3.89 (m, 1H), 3.47 (br s, 1H, OH), 2.65
(br s, 1H, OH), 1.18–1.94 (s-9H, 2m, 4H), 0.95 (t,
J = 7.3 Hz, 3H).13C NMR (125 MHz, CDCl3):
d = 157.7, 80.1, 66.7, 66.6, 66.0, 61.5, 30.7, 28.4, 19.2,
14.1. IR (cmꢁ1): 3380, 3297, 2974, 2940, 2872, 1680,
1396, 1162. ESI-MS: 246 (M + 1), 190, 172, 154, 146,
128, 116, 111.
4.6.5. (2S, 3S, 4R)-2-hydroxymethyl-3-hydroxy-4-
propyl-azetidinium trifluoroacetic salt (19)
3.1 mg (0.013 mmol) of diol 18 were dissolved in
0.2 ml of CH2Cl2 and the resulting solution cooled to
0 °C. Trifluoroacetic acid (0.1 ml) was added to this
solution and after 1.5 h the solution was concentrated
to dryness. The desired salt was obtained in 99% yield
1
(3.2 mg) as a pure material as analyzed by NMR. H
4.6.2. (2S, 3S, 4R)-N-(p-toluene-sulfonyl)-2-(tert-
butyldiphenylsilyloxymethyl)-4-propyl-azetidin-3-ol
(20a)
NMR (300 MHz, CD3OD): d = 4.57 (t, J = 5.9 Hz,
1H, H3), 4.39 (m, 2H, H2 and H4), 3.97 (dd, J = 12.5,
8.8 Hz, 1H), 3.83 (dd, J = 12.5, 4.4 Hz, 1H), 1.82(q,
J = 7.3 Hz, 2H), 1.36 (sex, J = 7.3 Hz, 2H), 0.99 (t,
J = 7.3 Hz, 3H). 13C NMR (75 MHz, CD3OD):
d = 67.8, 65.2, 65.0, 58.7, 29.3, 19.4, 14.2. IR (cmꢁ1):
3282 (br), 2969, 2876, 1680, 1196, 1142. ESI-MS: 146
(M + 1), 128, 116, 110, 98, 81, 60. HRMS m/z Calc.
for C9H16F3NO4 259.1031, Found: 259.1052.
1
50%, H NMR (300 MHz, CDCl3 + D2O): d = 7.24–
7.84 (14H, Ar), 4.31 (t, J = 7.3 Hz, 1H, H3), 4.11 (dd,
J = 11.7, 3.7 Hz, 1H), 3.92 (dd, J = 11.7, 2.2 Hz, 1H),
3.76–3.88 (m, 2H), 2.44 (s, 3H), 1.76–2.04 (m, 2H), 1.36
(sext., J = 7.3 Hz, 2H), 1.10 (s, 9H), 0.92 (t, J = 7.3 Hz,
3H). 13C NMR (75 MHz, CDCl3): d = 143.7, 135.6,
135.4, 132.2 (2s), 131.4, 129.9, 129.4, 128.0, 127.7, 67.7,
66.8, 65.0, 64.0, 30.9, 26.9, 21.7, 19.2, 18.8, 14.2. IR
(cmꢁ1): 3456, 3071, 3045, 2954, 2931, 2860, 1335, 1158,
1116, 1090, 701. HRMS m/z Calc. for C26H30NO4SSi
(M+-tBu) 480.1665, Found: 480.1653.
4.6.6. (2S, 3S, 4R)-2-hydroxymethyl-3-hydroxy-4-
propyl-azetidinium trifluoroacetic salt 19 from 20a
55.4 mg (0.10 mmol) of N-Ts-azetidin-3-ol 20a were
dissolved in 0.5 ml of dry DME and the resulting solu-
tion cooled to ꢁ78 °C. To this solution was added drop-
wise a dark-green solution of Na/naphthalene in dry
DME (prepared by the addition of 18.0 mg of Na in a
0.5 M solution of naphthalene (125.0 mg) in DME) until
the dark-green color persisted. After 30 min, brine was
added to the solution and the aqueous phase extracted
with ethyl acetate (3x). The organic phase was dried
(Na2SO4), concentrated in vacuum and the crude prod-
uct filtered in a small pad of silica (5% ethyl acetate/hex-
ane to remove naphthalene and then pure ethyl acetate to
remove the product). After removal of the ethyl acetate
by vacuum, the crude product was dissolved in 4.0 ml
of THF and the resulting solution cooled to 0 °C. Next,
1.5 equiv. of a 1.0 M solution of TBAF in THF were
added and the solution stirred for 3 h, followed by the
addition of trifluoroacetic acid. The solvent was removed
in vacuum and the crude product purified by flash col-
umn chromatography (50% MeOH/CHCl3), furnishing
13.0 mg of azetidine 19 (50% yield).
4.6.3. (2S, 3R, 4R)-N-(p-toluene-sulfonyl)-2-(tert-
butyldiphenylsilyloxymethyl)-4-propyl-azetidin-3-ol
(20b)
1
20%, H NMR (300 MHz, CDCl3 + D2O): d = 7.28–
7.70 (14H, Ar), 3.97 (t, J = 5.1 Hz, 1H, H3), 3.80–3.92
(m, 2H), 3.39–3.51 (m, 2H), 2.44 (s, 3H), 1.80 (m, 1H),
1.63 (m, 1H), 1.36 (m, 2H), 1.08 (s, 9H), 0.92 (t,
J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d = 143.7, 135.6, 133.2, 132.8, 132.0, 129.6 (2s), 128.2,
127.8, 70.4, 69.1, 63.4, 35.5, 26.9, 21.7, 19.4, 17.4, 14.1.
IR (cmꢁ1): 3490, 3075, 3052, 2962, 2931, 2860, 1339,
1154, 1112, 705. HRMS m/z Calc. for C26H30NO4SSi
(M+ ꢁ tBu) 480.1665, Found: 480.1643.
4.6.4. (2S, 3S, 4R)-N-(tert-butyloxycarbonyl)-2-
hydroxymethyl-4-propyl-azetidin-3-ol (18)
50 ll of a 1.0 M solution of TBAF in THF was added
to a stirred solution of 15.6 mg (0.032 mmol) of the

5646
A.C.B. Burtoloso, C.R.D. Correia / Journal of Organometallic Chemistry 690 (2005) 5636–5646
[6] For review in the chemistry of azetidin-3-ones, see: Y.
a
Acknowledgments
Dejaegher, N.M. KuzÕnenok, A.M. Zvonok, N. De Kimpe,
Chem. Rev. 102 (2002) 29.
[7] (a) A. Salgado, M. Boeykens, C. Gauthier, J. Declercq, N. De
Kimpe, Tetrahedron 58 (2002) 2763;
We thank FAPESP (Research Supporting Founda-
tion of the State of Sao Paulo) and CNPq, for financial
˜
support and a PhD fellowship.
(b) A. Salgado, M. Boeykens, C. Gauthier, Y. Dejaegher, G.
Verniest, C. Lopin, K.A. Tehrani, N. De Kimpe, Tetrahedron 59
(2003) 2231.
[8] N. Kise, H. Ozaki, N. Moriyama, Y. Kitagishi, N. Ueda, J. Am.
Chem. Soc. 125 (2003) 11591.
Appendix A. Supplementary data
[9] M.P. Doyle, M.A. McKervey, T. Ye, Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: from Cyclopro-
panes to Ylides, Wiley, New York, 1998.
[10] (a) M.P. Moyer, P.L. Feldman, H. Rapoport, J. Org. Chem. 50
(1985) 5223;
1H NMR, 13C NMR and IR spectra for all new com-
pounds. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.jorganchem.2005.07.016.
(b) G. Emmer, Tetrahedron 48 (1992) 7165;
(c) S. Hanessian, J. Fu, J.L. Chiara, R. Di Fabio, Tetrahedron
Lett. 34 (1993) 4157;
References
(d) J. Podlech, D. Seebach, Helv. Chim. Acta 78 (1995) 1238;
(e) S. Sengupta, D. Das, Synth. Commun. 28 (1998) 403;
´
(f) P. Desai, J. Aube, Org. Lett. 2 (2000) 1657;
[1] (a) J. Kobayashi, J. Cheng, M. Ishibashi, M.R. Walchli, S.
Yamamura, Y.J. Ohizumi, Chem. Soc. Perkin Trans. 1 (1991) 1135;
(b) K.A. Alvi, M. Jaspars, P. Crews, Bioorg. Biomed. Chem. Lett. 4
(1994) 2447.
[2] Some recent examples: (a) A. Marinetti, P. Hubert, J.P. Geneˆt,
Eur. J. Org. Chem. (2000) 1815;
(g) A. Pusino, A. Saba, G. Desole, Gazzeta Chimica Italiana 115
(1985) 33;
(h) J. Wang, Y. Hou, P.J. Wu, Chem. Soc. Perkin Trans. 1 (1999)
2277.
[11] J.R. Dyer, R.B. Randall, H.M. Deutsch, J. Org. Chem. 29 (1964)
3423.
(b) F. Couty, D. Prim, Tetrahedron: Asymmetry 13 (2002) 2619;
(c) G. Guanti, R. Riva, Tetrahedron: Asymmetry 12 (2001) 605;
(d) J. Wilken, S. Erny, S. Wassmann, J. Martens, Tetrahedron:
Asymmetry 11 (2000) 2143;
[12] T. Ye, A. McKervey, Tetrahedron 48 (1992) 8007.
[13] T. Aratani, Pure Appl. Chem. 57 (1985) 1839.
[14] Racemic and chiral diazo compound 6 (see Scheme 3) were
synthesized and submitted to the conditions described in
Scheme 4 (entry 10) for the N–H insertion reactions. After
HPLC analysis of the respective azetidin-3-ones, we found an
enantiomeric excess higher than 99% for the chiral compound,
demonstrating that no epimerization had occurred during the
two-step reaction.
[15] The results employing Cu(OAc)2 as catalysts (azetidin-3-one 8
(77%) compared with Cu(acac)2 (67%), Scheme 4) are very recent
in our laboratory. That is the main reason for using Cu(acac)2 as
catalyst in the synthesis of the azetidin-3-ones instead of
Cu(OAc)2.
(e) M. Shi, J.K. Jiang, Tetrahedron: Asymmetry 10 (1999) 1673.
[3] (a) T. Hiraki, Y. Yamagiwa, T. Kamikawa, Tetrahedron Lett. 36
(1995) 4841;
(b) H. Takikawa, T. Maeda, K. Mori, Tetrahedron Lett. 36
(1995) 7689;
(c) H. Yoda, T. Oguchi, K. Takabe, Tetrahedron: Asymmetry 7
(1996) 2113;
(d) A. Yashima, H. Takikawa, K. Mori, Liebigs Ann. 7 (1996)
1083;
(e) K. Mori, J. Heterocyclic Chem. 33 (1996) 1497;
(f) H. Yoda, T. Oguchi, K. Takabe, Tetrahedron Lett. 38 (1997)
3283;
(g) S. Knapp, Y. Dong, Tetrahedron Lett. 38 (1997) 3813;
(h) H. Takikawa, T. Maeda, M. Seki, J. Chem. Soc. Perkin Trans.
1 2 (1997) 97;
(i) G.Q. Lin, D.G. Liu, Heterocycles 47 (1998) 337;
(j) G.Q. Lin, D.G. Liu, Tetrahedron Lett. 40 (1999) 337;
(k) H. Yoda, T. Uemura, K. Takabe, Tetrahedron Lett. 44 (2003)
977.
[16] (a) D.F. Taber, K.K. You, A.L. Rheigold, J. Am. Chem. Soc. 118
(1996) 547;
(b) M.P. Doyle, L.J. Westrum, W.N.E. Wolthuis, M.M. See,
W.P. Boone, V. Bagheri, M.M. Pearson, J. Am. Chem. Soc. 115
(1993) 958;
(c) E. Nakamura, N. Yoshikai, M. Yamanaka, J. Am. Chem.
Soc. 124 (2002) 7181, and references cited therein.
[17] F.A. Davis, B. Yang, J. Deng, J. Org. Chem. 68 (2003) 5147.
[18] G.A. Rampel, P. Legzdins, H. Smith, G. Wilkinson, Inorg. Synth.
13 (1972) 90.
[19] D.P. Graddon, J. Inorg. Nucl. Chem. 14 (1960) 161.
[20] P. Garner, J.M. Park, J. Org. Chem. 52 (1987) 2361.
[21] D. Craig, M.B. Berry, Synlett (1992) 41.
[4] For a review on the synthesis of chiral azetidines, see: F. Couty,
G. Evano, D. Prim, Mini-reviews Org. Chem. 1 (2004) 133.
[5] (a) A.C.B. Burtoloso, C.R.D. Correia, Tetrahedron Lett. 45
(2004) 3355;
(b) A.C.B. Burtoloso, C.R.D. Correia, Synlett (2005) 1559.