Reductive ring opening of 2-azetidinones promoted by sodium borohydride

Article abstract of DOI:10.1016/j.tetlet.2006.01.103

Variously substituted 2-azetidinones 3 and 4 were reacted with sodium borohydride in aqueous isopropanol giving 3-aminopropan-1,2-dioles 5 and 7. Reaction extent was dependent upon the substitution pattern in the 3- and 4-positions of the 2-azetidinone ri

Full text of DOI:10.1016/j.tetlet.2006.01.103

Tetrahedron Letters 47 (2006) 2209–2211
Reductive ring opening of 2-azetidinones promoted
by sodium borohydride
Paola Del Buttero,* Giorgio Molteni and Maurizio Roncoroni
`
Universita degli Studi di Milano, Dipartimento di Chimica Organica e Industriale, via Golgi 19, 20133 Milano, Italy
Received 11 January 2006; revised 19 January 2006; accepted 19 January 2006
Available online 13 February 2006
Abstract—Variously substituted 2-azetidinones 3 and 4 were reacted with sodium borohydride in aqueous isopropanol giving
3-aminopropan-1,2-dioles 5 and 7. Reaction extent was dependent upon the substitution pattern in the 3- and 4-positions of the
2-azetidinone ring and revealed good correlation with carbonyl LUMO energies of starting 3.
Ó 2006 Elsevier Ltd. All rights reserved.
The 2-azetidinone (b-lactam) ring represent the key
structural feature of the main class of antibacterial
agents, namely the b-lactam antibiotics.1 In the light
of their relevance both in industrial and academic fields,
several strategies devoted to the synthesis of new b-lac-
tams have been developed,2 giving rise to a lot of com-
pounds featuring enhanced antibacterial activity3 or
better resistance towards b-lactamases.4 Within this
developing picture, new evidences on the chemical
behaviour of the 2-azetidinone ring should be highly
valuable. In this field, the reductive ring opening of
b-lactams giving b-amino alcohols have been exploited
in the presence of several hydrides, namely monochloro-
alane5 or lithium aluminium hydride.6 At a first glance,
sodium borohydride seems not a suitable reagent for
this transformation, since only one literature example
is available describing the ring fission of compound 17
(Fig. 1), which is strongly activated towards nucleophilic
attack by the presence of the N-benzyloxycarbamate
moiety. When tricarbonyl(g6-arene) chromium(0) com-
plex in the 4-position of the azetidinone ring acts as
the activating group, although an acyclic (ring-fission
COOtBu
NaBH4
tBuOOC
O
HO
(93%)
N
H
N
O
Ph
O
Ph
O
O
1
OH
OH
O
H
H
H
H
H
H
N
NaBH4
(97%)
Ar
Ar
Ar
Ph
PMP
Ph
Ph
PMP
+
:
N
N
O
O
O
PMP
70
30
2
F
OMe
Ar =
PMP =
NO2
Figure 1.
*
Corresponding author. Fax: +39 02 50314139; e-mail: paola.delbuttero@unimi.it
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.103

2210
P. Del Buttero et al. / Tetrahedron Letters 47 (2006) 2209–2211
Table 1. Reaction of 2-azetidinones 3 and 4 with NaBH4 in aq
derived) product was not isolated, its occurrence was
recently postulated by us in the sodium borohydride
promoted conversion 2-azetidinones ! dihydrobenzo-
pyranes.8 Less activated substrates are prone to side-
chain transformations, which leaves the 2-azetidinone
ring unchanged,9 as is shown in Figure 1 for the stereo-
selective carbonyl reduction of compound 2.10
isopropanola
Entry
R1
Products and yields (%)b
3
5
6
7
1
2
3
4
5
6
7
8
H
Me
F
NO2
H
Me
F
85
68
29
13
—
—
—
—
15
32
71
87
—
—
—
—
—
—
—
—
26
8
—
—
—
—
74
92
95
95
The aim of this letter is to show that sodium boro-
hydride can behave as an effective reagent in the reduc-
tive ring opening of b-lactams, and to illustrate which
structural features of the starting four-membered
heterocycle allows the above transformation.
5
5
NO2
a 5 mol equiv of NaBH4.
b As determined from 1H NMR analyses of reaction crudes.
(3S*,4S*)-2-Azetidinones 3 and 4 were synthesized
through standard [2+2] (Staudinger) cycloaddition as
is depicted in Scheme 1. Subsequent treatment of the
latter products with sodium borohydride11 gave 2-phen-
oxy-3-aryl-3-aminopropan-1-ols 512 or 2-hydroxy-3-
aryl-3-aminopropan-1-ols 713 according to the substitu-
tion pattern in the 3-position of the 2-azetidinone ring.
Products and product yields are reported in Table 1.
Mixtures of the starting b-lactam and the open-chain
product 5 were obtained from 3-phenoxy-2-azetidinones
3 (Table 1, entries 1–4). It can be added that the ratio 5:3
increases according to the electron withdrawal character
of R1. The behaviour of 3-acetoxy-2-azetidinones 4 was
different since (i) sodium borohydride first hydrolizes 4
to 3-hydroxy-2-azetinones 6, and (ii) open-chain prod-
ucts 7 were obtained with very good yields indepen-
dently from the electronic features of R1 (Table 1,
entries 5–8). The rationale to these findings are apparent
from the carbonyl LUMO energies of both 3 and 4 cal-
culated with the AM114 method (Table 2).15 Decreasing
of the LUMO energies in the series 3a!3d justifies the
better reactivity of electron-poor substrates towards
hydride, while the much lower LUMO energies of 4
accounts for their better reactivity and the lack of sensi-
tivity towards R1.
Table 2. AM1 computed carbonyl LUMO energies of 2-azetidinones 3
and 6
R1
3 E (eV)
6 E (eV)
H
Me
F
+0.346
+0.336
+0.321
+0.263
ꢀ3.422
ꢀ3.408
ꢀ3.448
ꢀ3.647
NO2
The facile reductive ring opening of 2-azetidinones 3 and
4 points to some kind of complexation between the
substrate and the borohydride reagent. To this point,
we perceived model A (Fig. 2) as a reasonable
reaction intermediate. Structure optimization of A at
the AM114 level showed two main interactions: (i)
between boron and the oxygen in the 3-position of the
˚
2-azetidinone ring (distance B–O = 1.85 A), and (ii) be-
tween a hydride and the LUMO of the aromatic ring
˚
in the 4-position (distance H–Ar = 2.59 A). This latter
p-H interaction, which finds precedents in the litera-
ture,16 allows one hydride to be close enough to the
RO
+
R1
N
O
Cl
PMP
Et3N
R1
R = Ph
PhO
PMP
NH
OH
0 C
˚
5
RO
NaBH4
R1
N
R1
PMP
HO
O
O
PMP
R = Ac
HO
1
R
NH
OH
3 (R = Ph), 4 (R = Ac)
N
PMP
6
7
a: R1 = H, b: R1 = Me, c: R1 = F, d: R1 = NO2
Scheme 1.

P. Del Buttero et al. / Tetrahedron Letters 47 (2006) 2209–2211
2211
2. (a) Sammes, P. G. Chem. Rev. 1976, 76, 113; (b) Hart, D.
J.; Ha, D. C. Chem. Rev. 1989, 89, 1447.
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Synlett 1997, 2776.
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Tetrahedron: Asymmetry 2005, 16, 971.
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1995, 36, 4301; (b) Kawabata, T.; Itoh, K.; Hiyama, T.
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Figure 2.
˚
2-azetidinone carbonyl (distance H–C = 2.14 A) to
promote reaction.
`
A.; Cossıo, F. P.; Aizpurna, J. M.; Mielgo, A.; Aurre-
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Tetrahedron 2003, 59, 5259.
On the basis of the above findings, it is apparent that
b-lactams can undergo reductive ring opening in the
presence of sodium borohydride provided that two
structural features are met. First, a donor heteroatom
in the 3-position of the 2-azetidinone ring should be
present in order to allow complexation with boron.
Second, an aromatic ring in the 4-position and cis with
respect to the donor heteroatom is required to ensure
the p-H interaction, which provides the arrangement
of intermediate A.
11. For a typical run: A suspension of 3 or 4 (0.87 mmol) in
isopropanol (11 mL) was treated with sodium borohydride
(0.16 g, 4.3 mmol) in water (2 mL) and then stirred under
nitrogen for 20 h. The crude was partly evaporated under
reduced pressure and taken up with dichloromethane
(40 mL). The organic layer was washed with water to
neutrality, dried over sodium sulfate and evaporated. The
residue was chromatographed on silica gel column giving
open-chain products 5 or 7.
12. Selected 1H NMR data of compounds 5 in CDCl3
solutions. Compound 5a: d 3.75 (3H, s), 3.80 (1H, dd, J
11.8, 4.2), 3.95 (1H, dd, J 11.8, 4.8), 4.5–4.6 (1H, m), 4.75
(1H, d, J 4.9), 6.6–7.5 (14H, m). Compound 5b: d 2.53
(3H, s), 3.70 (3H, s), 3.80 (1H, dd, J 11.6, 4.4), 3.95 (1H,
dd, J 11.6, 5.4), 4.4–4.5 (1H, m), 4.96 (1H, d, J 4.0), 6.5–
7.4 (13H, m). Compound 5c: d 3.75 (3H, s), 3.80 (1H, dd, J
11.6, 4.2), 3.95 (1H, dd, J 11.6, 5.2), 4.5–4.6 (1H, m), 4.97
(1H, d, J 4.3), 6.6–7.5 (13H, m). Compound 5d: d 3.70
(3H, s), 4.0–4.1 (1H, m), 4.8–4.9 (1H, m), 5.5–5.6 (1H, m),
4.97 (1H, d, J 4.3), 6.5–7.9 (13H, m).
To test the latter rules, 2-azetidinones 8, 9 and 10 were
synthesized and then submitted to treatment with
sodium borohydride. Unchanged starting products were
isolated according to our expectations.
Ph
Ph
O
Ph
PhO
O
Ph
N
N
N
13. Selected 1H NMR data of compounds 7 in CDCl3
solutions. Compound 7a: 3.60 (1H, dd, J 10.7, 6.0), 3.70
(3H, s), 3.75 (1H, dd, J 10.7, 3.7), 3.9–4.0 (1H, m), 4.42
(1H, d, J 6.5), 6.5–7.3 (9H, m). Compound 7b: 2.42 (3H,
s), 3.60 (1H, dd, J 11.4, 6.0), 3.70 (3H, s), 3.75 (1H, dd, J
11.4, 3.7), 3.9–4.0 (1H, m), 4.70 (1H, d, J 6.0), 6.5–7.4 (8H,
m). Compound 7c: 3.60 (1H, dd, J 10.7, 5.2), 3.70 (3H, s),
3.8–4.0 (2H, m), 4.70 (1H, d, J 6.6), 6.7–7.3 (8H, m).
Compound 7d: d 3.70 (3H, s), 3.8–4.1 (3H, m), 5.35 (1H, d,
J 5.8), 6.5–7.9 (8H, m).
O
PMP
PMP
PMP
8
9
10
Acknowledgements
Thanks are due to MURST (COFIN) for financial
support.
14. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart,
J. P. J. Am. Chem. Soc. 1985, 107, 3902.
15. As implemented in the HyperChem 7.04 Professional
package of programs. Hypercube, 2002.
References and notes
1. The Chemistry of b-Lactams; Page, M. I., Ed.; Chapman
16. Tarakeshwar, P.; Choi, H. S.; Kim, K. S. J. Am. Chem.
Soc. 2001, 123, 3323.
and Hall: London, 1992.