4- Unsubstituted azetidin-2-ones

The reactions of AyV-dialkylhydrazoncs with benzoyloxyketene <2002AGE831> and aminoketene <2004OL2749> precursors appear to be a new general approach to the enantioselective synthesis of 4-substituted 3-alkoxyazetidin-2-ones and 3-aminoazetidin-2-ones. Such hydrazones 488, derived from formaldehyde, afforded 4-unsubstituted azetidin-2-ones 489 (Equation 198) in 80-96% yields and dr s up to 99 1 <2004CEJ6111>. 

In analogy with penams, 3a-bromo, 3,3-dibromo, and 3-unsubstituted azetidin-ones can be used as substrates for the stereoselective introduction of the hydroxyethyl group. A first set of compounds, the 4,7-lactams 95, are historical-... 

O-Alkylation of A-unsubstituted /3-lactams to give the corresponding 2-alkoxy-l- etines can be achieved by reaction of the azetidin-2-ones with hard electrophiles (trialkyloxonium tetrafluoroborates) followed by treatment with base (cf. Section 5.09.4.3.1) (67JHC619, 69LA(725)124). In contrast, reaction of the A-unsubstituted azetidin-2-ones (73) or their derived anions with a variety of softer electrophiles results in A-substitution, and some representative reactions are illustrated in Scheme 7. 

AT-Unsubstituted azetidin-2-ones are versatile intermediates in the preparation of a variety of novel /3-lactam containing systems. They are usually made either by reductive dechlorosulfonylation of alkene/chlorosulfonyl isocyanate cycloadducts cf. Section 5.09.3.3.2), which... 

O-Alkylation of the readily available iV-unsubstituted azetidin-2-ones (/3-lactams) constitutes a versatile route to 2-alkoxy-l-azetines (cf. Section 5.09.3.2.3). Thus treatment of the /3-lactams (266) with trialkyloxonium tetrafluoroborates followed by basification affords the 2-alkoxy-l-azetines (267) in moderate yields (67JHC619,69LA(725)124). Similar treatment of the azetidine-2-thiones (268) (available from thiation of the corresponding /3-lactams with phosphorus pentasulfide) affords the analogous 2-ethylthio-1-azetines (269) (67JHC619), which are generally more stable than their 2-alkoxy analogues. 

Lithium ester enolate addition to imines has been used for the construction of optically active p-lactams, e.g. 64 and the lithium enolates have been found to be superior to other metal derivatives for both yields and diastereoselectivity in some cases <00H(53)1479>. Immobilized lithium ester enolates have been utilized for the first time <00OL907> and soluble polymer supported imines were used to obtain N-unsubstituted azetidin-2-ones under mild conditions <00CEJ193>. Both lithium and titanium enolates have been employed to obtain cholesterol absorption inhibitors <99TA4841>. Lithium ynolates 65 add to imines to provide P-lactams in good to excellent yield <00TL5943>. 

The reaction of imines with 2-pyridyl thioesters in the presence of aluminium tribromide or ethylaluminium dichloride afforded /ra r-3,4-disubstituted azetidin-2-ones < 1996T2583>. Similar stereoselective addition of silylketene thioacetals to imines is known in the presence of Lewis acids <1996T2573>. An indium-mediated reaction of ethyl bromoacetate with imines yielded 3-unsubstituted azetidin-2-ones in reasonable yields (Equation 195) <2000J(P1)2179>. 

Poly(P-alanine) (PA3) cannot be obtained by chemically initiated ROP of the unsubstituted azetidin-2-one (p-lactam), but only by anionic isomerization polymerization of acrylamide. The latter synthesis, however, generally leads to stmcturally irregular polyamide 3. On the contrary, the polymerization of p-lactams may be accessible by novel enzymatic routes. 

Scheme 28 Reaction pathway in the enzymatic formation of poly(b-alanine) from unsubstituted azetidin-2-one.

It is often necessary to prepare /3-lactams with particular substituents at N-1, C-3 and C-4, e.g. in the preparation of fused /3-lactams from monocyclic precursors. For reasons of space it is not possible to give an exhaustive list of the variously substituted /3-lactams available however, Table 4 summarizes the most general routes to /3-lactams bearing particular substituents at C-3 and C-4. -Substitution of azetidin-2-ones has already been dealt with cf. Section 5.09.3.2.3). N-Unsubstituted /3-lactams and protected 3-amino-/3-lactams are particularly important synthetic intermediates and methods of preparing these are discussed below. 

The synthesis of ot-branched 3-amino-4-unsubstituted (3-lactams (IV, Fig. 3) could be performed efficiently via an asymmetric alkylation of a single 3-oxazoli-dinyl azetidin-2-one [248]. 

N-Substituted azetidin-2-ones are more stable than their unsubstituted counterparts and as a result are more resistant to nucleophilic additions. However, treatment of either 4 - or 4a-chloroazetidinone (101)... 

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