2-Azetidinones 3-silylation

Merck s thienamycin synthesis commences with mono (V-silylation of dibenzyl aspartate (13, Scheme 2), the bis(benzyl) ester of aspartic acid (12). Thus, treatment of a cooled (0°C) solution of 13 in ether with trimethylsilyl chloride and triethylamine, followed by filtration to remove the triethylamine hydrochloride by-product, provides 11. When 11 is exposed to the action of one equivalent of tm-butylmagnesium chloride, the active hydrogen attached to nitrogen is removed, and the resultant anion spontaneously condenses with the electrophilic ester carbonyl four atoms away. After hydrolysis of the reaction mixture with 2 n HC1 saturated with ammonium chloride, enantiomerically pure azetidinone ester 10 is formed in 65-70% yield from 13. Although it is conceivable that... 

Azetidinones.1 The dianion (BuLi) of 1 condenses with the N-aryl aldimine 2 to provide a 1 1 mixture of the trans- and cis-adducts 3. The adducts (3) can be converted by Mitsunobu silylation (inversion), oxidative degradation of the side... 

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

A further application of silylated amino acids is the formation of /3-lactams by treating N-TMS-0-amino acid-TMS-esters (497) with Grignard reagents under cycli-zation262 (Scheme 74). From N-TMS-a-phenyl-/ -alanin-TMS-ester (497) via the silylated product (498), 3-phenyl-2-azetidinone (499) can be obtained. 

A similar process was used to silylate l,4-bis(trimethylsilyl)azetidinone in position 3... 

Substitution of the silyl group for a tin group gives access to azetidinones having the SMA fragment in the skeleton.169... 

In an effort to cleave the silyl group (see Section VI.B.2), 4-trimethylsilyl azetidinone was treated with tetrabutylammonium fluoride, TBAF, in the presence of acetaldehyde. The corresponding aminal was obtained instead in 65% yield.223... 

The amidic proton of the same azetidinone has been silylated in a classical way, almost quantitatively, using chlorosilane/triethylamine mixture at 0 °c.122a... 

The same technique can be applied to regioselectively prepare 4-alkoxy substituted azetidinones. Non-silylated azetidinones have oxidation potentials, which are too high for this process. Introduction of a silyl group lowers these potentials, rendering the reaction easier and more regiospecific. Note that in the case of /V-benzyl azetidinones, the methoxylation reaction occurs also at the benzylic position.12213 355... 

The enolate of azetidinone 266 underwent a 1,4-silyl migration from the carboxylate oxygen to the C-3 carbon atom in THF at —75°C providing exclusively the trans-/Tsilyl carboxylic acid 267 (equation 166). The stereoselectivity was explained by the facile base-catalyzed epimerization of the initial product cis-267 to the more stable trans-267412. 

Cleavage of an azetidinone epoxide.1 MgBr2, prepared from Mg with BrCH2CH2Br, cleaves the epoxide 1 regiospecifically to the diastereomeric bromo-hvdrins 2. The N-silyl derivative of 1 is stable under the same conditions. The ketone corresponding to 2 is a useful precursor to a carbapenem. 

Schering-Plough Corp, has used an oxazolidinone in its synthesis of the cholesterol adsorption inhibitor (+)-SCH 54016 (24) (Scheme 7) [51], Condensation of an acid chloride intermediate with the (7 )-phenylglycine-derived Evans auxiliary followed by reaction of the titanium enolate with -(4-methoxybenzyh-dene)anihne gave the intermediate 25. This was silylated and treated with TBAF, resulting in removal of the auxiliary and cyclization to form the 2-azetidinone ring. The stereochemistry was exclusively trans. The azetidinone was then converted to the bromide, followed by intramolecular alkylation to form SCH 50416 in > 99% ee. 

The use of TMSOTf in the reaction of silyl ketene acetals with imines offers an improvement over other methods (such as Ti - or Zn -mediated processes) in that truly catalytic amounts of activator may be used (eq 17) this reaction may be used as the cmcial step in a general s5mthesis of 3-(l -hytIroxyethyl)-2-azetidinones (eq 18). ... 

Since the first work of Ojima and coworkers [83] on the reaction between silyl ketene acetals 169 and imines 170, to produce P-aminoeaters 171 and P-lactams 172 (Scheme 28), several research groups have utilized such approach to the construction of the azetidinone ring [84]. 

In the Kaneka approach [12], silyl enol ether 14 is obtained from the starting butyrate by sequential 0-protection, reduction to the aldehyde and treatment with TMS-Cl/TEA. Cycloaddition with CSI and reductive N-de-chlorosulfonylation with either LAH or PhSH affords azetidinone 17. Much emphasis is placed on the conversion 17 11, since 4-hydroxyazetidinones... 

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