Highly syn-diastereoselective synthesis of NH-3-benzyloxy-4-aryl-azetidin-2-ones via a two-step Staudinger reaction

Article abstract of DOI:10.1055/s-1998-1793

New conditions for the Staudinger reaction provide NH-3-benzyloxy-4-aryl-β-lactams in good yields with complete cis-diastereoselectivity.

Full text of DOI:10.1055/s-1998-1793

August 1998
SYNLETT
843
Highly syn-Diastereoselective Synthesis of NH-3-Benzyloxy-4-aryl-azetidin-2-ones via a
Two-Step Staudinger Reaction
Sergio Bacchi, Alessandro Bongini, Mauro Panunzio* and Marzia Villa
CSFM-C.N.R. and University of Bologna, Dipartimento di Chimica “G. Ciamician”, Via Selmi 2, 40126 Bologna, Italy
Fax +39-51-25 94 56; Bitnet: panunzio@ciam.unibo.it
Received 11 May 1998
Abstract: New conditions for the Staudinger reaction provide NH-3-
benzyloxy-4-aryl-β-lactams in good yields with complete cis-
diastereoselectivity.
iminic carbon which stabilises the E-anti azadiene. A similar effect has
already been invoked to explain the cis-diastereoselectivity observed in
7
the classical Staudinger cycloaddition reactions.
Preliminary
semiempirical (PM3) or ab initio (HF/3-21G*) calculations on a model
compound have confirmed the preference (2.5 kcal/mol) for the reported
(E-anti )-4 azadiene structure over the corresponding (Z-anti) structure.
Diastereochemically pure cis-3-hydroxy-4-aryl-azetidin-2-ones are
useful intermediates for the preparation of α-hydroxy-β-aminoacids,
including the biologically important phenylisoserine, side chain of
paclitaxel (Fig. 1), one of the most promising new drugs in cancer
chemotherapy, recently approved for treatment of metastatic ovarian and
breast cancer. Other researchers have revealed its effects against non-
small cell lung cancer, head and neck cancer, glioblastoma and
c) Despite considerable efforts, we could not isolate and characterise the
postulated intermediate azadiene 4 so far. Work is continuing towards
the elucidation of the structure of this intermediate since knowledge of
the stereochemistry of 4 may clarify the reaction mechanism and lead to
a rationale for the surprising stereochemical outcome of the reaction.
1
oesophageal cancer.
Figure 1
Recently, it has been found that paclixatel A and related derivatives may
be obtained from the renewable material, 10-deacetyl baccatin-III C, by
2
its coupling with suitable protected β-lactams 5. Therefore, the
development of short and practical synthetic routes towards this class of
intermediates, characterised by the presence of different aryl groups at
3
C-4, has become very important. Among the many synthetic methods
available for the preparation of the key β-lactam intermediates, the most
popular are the [2+2] cycloaddition reaction of imines and ketenes,
4a,b
known as the Staudinger reaction,
condensation route.
or the ester enolates-imine
4c-e
Recently, we have reported a new variant of
5
Staudinger reaction, starting from N-trimethylsilyl imines, which
allows the preparation of NH azetidinone derivatives avoiding the usual
deprotection-step of the p-methoxy-phenyl group (or its equivalent)
directly linked to the β-lactam nitrogen. In this paper we report our
preliminary results on the preparation of cis-3-benzyloxy-4-aryl-
azetidin-2-ones with a complete cis-diastereoselectivity. The results,
6
shown in Table 1, warrant some comments:
Scheme 1
a) The relative stereochemistry of the substituents at the β-lactam ring is
invariably cis regardless of the nature of the R group on the imine. This
is in contrast to the results obtained using ketenes derived from N-
amido-glycine, in which a complete trans diastereoselectivity has been
The conversion of compound rac-5a into the enantiopure
phenylisoserine, according reported protocols, may represent a useful
application of our methodology.
8
5a,b
observed.
b) Cyclization to the β-lactam ring is faster and proceeds under much
milder conditions (see experimental part) than in the case of the amido-
glycine derivatives. In that case a stable azadiene intermediate was
isolated in the Z-anti form. A conrotatory ring closure gave rise to the
trans product. Since the real difference between the amido-glycine
derivative and the benzyloxy-derivative is the presence of an amidic
nitrogen versus an ethereal oxygen, we can postulate the possible
formation of a weak electrostatic bond between ethereal oxygen and the
Scheme 3

844
LETTERS
SYNLETT
Work is in progress to apply this methodology to enantiopure β-lactam
(e) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, H.Y.; Sun,
derivatives as well as to fully clarify the reaction mechanism.
M.C.; Brigaud, T. Tetrahedron 1992, 48, 6985-7012.
(5) (a) Bandini, E.; Martelli, G.; Spunta, G.; Bongini, A.; Panunzio,
M., Tetrahedron Lett. 1996, 37, 4409-4412. (b) Bandini, E.;
Martelli, G.; Spunta, G.; Panunzio, M., Synlett 1996, 1017-1018.
(c) For preparation and application of N-trialkylsilylimines in
organic synthesis see: Panunzio, M.; Zarantonello, P., Org.
Process Res.Dev. 1998, 2, 49-59.
Acknowledgement: Financial support was provided by "Progetto
Strategico sulle Applicazioni Industriali della Tecnologia delle
Microonde" - CNR Rome". M.V. thanks GlaxoWellcome, Verona, for
financial support.
(6) General procedure : To a solution of aldehyde 1 (1 mmol) in
hexane (5 ml) was added LiHMDSA (1 mL of 1M solution in
THF) at 0°C. The reaction mixture was allowed to reach r.t.
spontaneously while the stirring was continued for 1 h. TMSCl
(1.1 mmol) was added in one portion and the reaction mixture
further stirred for 1 h. A white precipitate formed. The solution
was cooled at 0°C and triethylamine (1 mmol) was added in one
portion. The benzyloxyacetyl chloride 3 (1mmol), dissolved in
toluene (3 mL), was added dropwise. Stirring was maintained for
1 h while a new copious precipitate appeared. The precipitate was
filtered under argon, the solvent removed in vacuo,
dichloromethane (10 mL) was added and the resulting pale yellow
solution was stirred overnight at r.t. The crude mixture was poured
into a 1 N HCl solution and extracted with ethyl acetate. Flash
chromatography of the residue (cyclohexane/ethyl acetate 1/1)
yielded the pure isolated cis-N-unsubstituted-3-benzyloxy-4-aryl-
β-lactams 5 in the yields reported in Table 1.
References and Notes
(1) For a review see: Nicolaou, K.C.; Day, W.-M.; Guy, R.K. Angew.
Chem., Int. Ed. Engl. 1994, 33, 15-44.
(2) Holton, R.A.; Kim, H.-B.; Somoza, C.; Liang, F.; Biediger, R.J.;
Boatman, D.P.; Shindo, M.; Smith, C.C.; Kim, S.; Nadizadeh, H.;
Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K.K.;
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Vander Velde, D.G. J. Org. Chem. 1996, 61, 2664-2676 and ref.
therein cited.
(3) For recent syntheses of phenylisoserine see: (a) Song, C.E.; Lee,
S.W.; Roh, E.J.; Lee, S.; Lee, W.-K. Tetrahedron: Asymmetry
1998, 9, 983-992. (b) Li, G.; Sharpless, K.B. Acta Chem. Scand.
1996, 50, 649-651 and references therein cited. See also ref. 5e.
(4) (a) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of β-
Lactams; G. Georg, Ed.; VCH: New York, 1993; pp 318-323.
(b) Birkofer, L.; Schramm, J. Liebigs Ann. Chem. 1977, 760-766.
(c) Panunzio, M.; Cozzi, P.G.; Kretz, C.M.; Bandini, E.; Martelli,
G. In Topics in Heterocyclic Systems- Synthesis, Reactions and
Properties, Attanasi, A.O. and Spinelli, G. Eds.; Research
Signpost, Trivandrum, 1996; pp 119-140. (d) Colvin, E.W.;
McGarry, D.; Nugent, J.M. Tetrahedron 1988, 44, 4157-4172.
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C.J. J. Org. Chem. 1993, 58, 1068-1075.